Synthetic Molecular Motors and Mechanical Machines - Engineering ...

Reviews 

Molecular Devices 

DOI: 10.1002/anie.200504313 

Synthetic Molecular Motors and Mechanical Machines 

Euan R. Kay, David A. Leigh,* and Francesco Zerbetto* 

Keywords: 

molecular devices · nanotechnology · 

noncovalent interactions · 

supramolecular chemistry 

Angewandte 

Chemie 

D. A. Leigh, F. Zerbetto, and E. R. Kay 

72 www.angewandte.org 2007 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2007, 46, 72 – 191


The widespread use of controlled molecular-level motion in key 

natural processes suggests that great rewards could come from 

bridging the gap between the present generation of synthetic 

molecular systems, which by and large rely upon electronic and 

chemical effects to carry out their functions, and the machines of 

the macroscopic world, which utilize the synchronized movements 

of smaller parts to perform specific tasks. This is a scientific 

area of great contemporary interest and extraordinary recent 

growth, yet the notion of molecular-level machines dates back to a 

time when the ideas surrounding the statistical nature of matter 

and the laws of thermodynamics were first being formulated. Here 

we outline the exciting successes in taming molecular-level 

movement thus far, the underlying principles that all experimental 

designs must follow, and the early progress made towards utilizing 

synthetic molecular structures to perform tasks using mechanical 

motion. We also highlight some of the issues and challenges that 

still need to be overcome. 

1. Design Principles for Molecular-Level Motors and 

Machines 

In recent years chemists have demonstrated imagination 

and considerable skill in the design and construction of 

synthetic molecular systems in which positional displacements 

of submolecular components result from moving 

downhill in terms of energy. [1] But what are the structural 

features necessary for molecules to use chemical energy to 

repetitively do mechanical work? How can we make a 

molecular machine that pumps ions to reverse a concentration 

gradient,for example,or moves itself uphill in terms of 

energy? How can we make nanoscale structures that traverse 

a predefined path across a surface or down a track by 

responding to the nature of their environment so as to change 

direction? How can we make a synthetic molecular motor 

that rotates against an applied torque? Artificial compounds 

that can do such things have yet to be realized. Moreover,and 

perhaps more surprisingly given that nature has developed 

such machines and refined them to a high degree of efficiency, 

the literature is still largely bereft of the fundamental 

guidelines necessary to invent them. In this Review we try 

to address this deficiency by using theory to outline,develop, 

and present the underlying mechanisms and principles 

required for future generation synthetic molecular-level 

machine systems alongside the current experimental state of 

the art. 

Perhaps inevitably in an emerging field,there is not even a 

clear consensus as to what constitutes a molecular machine 

and what differentiates them from other molecular devices. 

Initially,the categorization of molecules as machines by 

chemists was purely iconic—the structures “looked” like 

pieces of machinery—or they were so-called because they 

carried out a function that in the macroscopic world would 

require a machine to perform it. Many of the chemical 

systems first likened to pistons and other machines were 

Angew. Chem. Int. Ed. 2007, 46, 72 – 191 2007 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim 

From the Contents 

1. Design Principles for Molecular-Level 

Motors and Machines 73 

2. Controlling Motion in Covalently 

Bonded Molecular Systems 85 

3. Controlling Motion in 

Supramolecular Systems 99 

4. Controlling Motion in Mechanically 

Bonded Molecular Systems 101 

5. Molecular-Level Motion Driven by 

External Fields 128 

6. Self-Propelled “Nanostructures” 132 

7. Molecular-Level Motion Driven by 

Atomically Sharp Tools 134 

8. From Laboratory to Technology: 

Towards Useful Molecular Machines 139 

9. Artificial Biomolecular Machines 157 

10. Conclusions and Outlook 163 

simply host–guest complexes in which the binding could be 

switched “on” or “off” by external stimuli such as light. [1] 

Whilst such studies were instrumental in popularizing the 

notion of molecular-level machines amongst chemists,it is fair 

to say (with considerable hindsight [2] ) that the effects of scale 

tell us that supramolecular decomplexation events have little 

in common with the motion or function of a piston (the 

analogy is somewhat better applied to shuttling within a 

rotaxane architecture because the components are always 

kinetically associated,but the implication of imparting 

momentum is still unfortunate). Similarly,a photosensitizer 

is not phenomenologically related to a “light-fueled motor”. 

Here we choose to differentiate machines from other devices 

on the basis that the etymology and meaning of “machine” 

generally implies mechanical movement—that is,a net 

nuclear displacement in the molecular world—which causes 

something useful to happen. Thus,for our purposes,“molec- 

[*] E. R. Kay, Prof. D. A. Leigh 

School of Chemistry 

University of Edinburgh 

The King’s Buildings, West Mains Road, Edinburgh EH93JJ (UK) 

Fax: (+ 44)131-650-6453 

E-mail: david.leigh@ed.ac.uk 

Prof. F. Zerbetto 

Dipartimento di Chimica “G. Ciamician” 

Università di Bologna 

v. F. Selmi 2, 40126 Bologna (Italy) 

Fax: (+ 39)051-209-9456 

E-mail: francesco.zerbetto@unibo.it 


Chemie 

73

Reviews 

ular machines” are a defined subset of “molecular devices” 

(functional molecular systems) in which some stimulus 

triggers the controlled,large amplitude or directional 

mechanical motion of one component relative to another 

(or of a substrate relative to the machine) which results in a 

net task being performed. Accordingly,we shall not discuss 

here supramolecular complexes in which the components are 

able to exchange with others in the bulk,or systems that 

function solely through changes in their electronic structure. 

Rather we will limit our scope to mechanical molecular-level 

devices,systems that feature—or attempt to feature—a 

degree of control over the motion of the components or 

substrates. The examples are chosen to help demonstrate the 

requirements for performing mechanical tasks at the molecular 

level. 

1.1. Molecular-Level Machines and the Language Used to 

Describe Them 

Language—especially scientific language—has to be suitably 

defined and correctly used to accurately convey concepts 

Euan Kay was born in Lanarkshire (Scotland) 

and educated at Hutchesons’ Grammar 

School. He received his MChem from 

the University of Edinburgh in 2002. He is 

currently a Carnegie Trust Scholar working 

towards a PhD in the group of David Leigh 

on developing and demonstrating mechanisms 

for the control of molecular-level 

motion in mechanically interlocked 

molecules. 

David Leigh was born in Birmingham (UK) 

and obtained his BSc and PhD from the 

University of Sheffield. After postdoctoral 

research at the NRC of Canada in Ottawa 

(1987–1989) he returned to the UK as a 

lecturer at UMIST. In 1998 he moved to the 

University of Warwick, and in 2001 he took 

up the Forbes Chair of Organic Chemistry at 

the University of Edinburgh. He holds both 

an EPSRC Senior Research Fellowship and a 

RoyalSociety-Wolfson Research Merit 

Award, and is a Fellow of the Royal Society 

of Edinburgh, Scotland’s National Academy 

of Science and Letters. His research interests include molecular-level 

motors and machines. 

Francesco Zerbetto received his PhD from 

the University of Bologna in 1986. From 

1986 to 1990 he was a postdoctoralresearch 

associate at the NationalResearch Council 

of Canada in Ottawa. He is currently Professor 

of PhysicalChemistry at the University of 

Bologna. His current research interests focus 

on the simulation of large systems that 

range from mechanically interlocked molecules, 

to fullerenes and nanotubes, to the 

interface between inorganic surfaces and 

organic materials. He is the author of more 

than 200 papers. 

in a field. Nowhere is the need for accurate scientific language 

more apparent than in the discussion of the ideas and 

mechanisms by which nanoscale machines could—and do— 

operate. [3] Much of the terminology used to describe molecular-level 

machines has its origins in the observations of 

physicists and biologists,but their findings and descriptions 

have at times been misunderstood or under-appreciated by 

chemists. Similarly,the chemistry of molecular systems can 

sometimes be overlooked by other disciplines. [4] 

As mechanism replaces imagery as the driving force 

behind advances in this field,it may be helpful for the 

terminology used to discuss molecular-level machine systems 

to become more phenomenologically based. When describing 

molecular behavior scientifically,the standard dictionary 

definitions meant for everyday use are not always appropriate 

for a regime that the definitions were never intended to cover. 

The difference between a “motor” and a “switch” as basic 

molecular machine types,for example,is significant because 

“motor” and “switch” become descriptors of very different 

types of behavior at molecular length scales,not simply iconic 

images (Figure 1). A “switch” influences a system as a 

function of state whereas a “motor” influences a system as a 

function of the trajectory of its components or the substrate. 

Returning a molecular-level switch to its original position 

undoes any mechanical effect it has on an external system 

(naturally,the molecules heat up their surroundings as the 

energy from the switching stimulus is dissipated); when the 

components of a rotary motor return to their original position 

through a different pathway to the one they left by (namely,a 

3608 directional rotation),a physical task performed by the 

machine is not inherently undone (for example,the rotating 

components could be used to wind up a polymer chain). 

This difference is profound and the terms really should 

not be used interchangeably as sometimes happens in the 

chemistry (but not physics [5] or biology) literature. That is not 

to say that molecular switches cannot use chemical energy to 

do mechanical work. They can,but it is undone by resetting 

the switch to its original state. The key reason why this point is 

important is that switches cannot use chemical energy to 

repetitively and progressively drive a system away from 

equilibrium,whereas a motor can. [6] Other molecular machine 

types,also differentiated on the basis of their fundamental 

behavior,can also be identified (see Section 4.4). It is an 

accurate reflection of the current state of the art that the vast 

majority of the molecular-level machines discussed in this 

Review are switches,not motors. Similarly,thus far only 

“influence-as-a-function-of-state” rather then “influence-asa-function-of-trajectory” 

molecular-level machines have been 

developed to the level that they can be exploited to perform 

tasks in the outside world. 

1.2. The Effects of Scale 


The path towards synthetic molecular machines can be 

traced back nearly two centuries to the observation of effects 

that pointed directly to the random motion experienced by all 

molecular-scale objects. In 1827,the Scottish botanist Robert 

Brown noted through his microscope the incessant,haphaz- 



Figure 1. The fundamental difference between a “switch” and a 

“motor” at the molecular level. Both translational and rotary switches 

influence a system as a function of the switch state. They switch 

between two or more, often equilibrium, states. Motors, however, 

influence a system as a function of the trajectory of their components 

or a substrate. Motors function repetitively and progressively on a 

system; the affect of a switch is undone by resetting the machine. 

a) Rotary switch. b) Rotary motor. c) Translational switch. d) Translational 

motor or pump. 

ard motion of tiny particles within translucent pollen grains 

suspended in water. [7] An explanation of the phenomenon— 

now known as Brownian motion or movement—was provided 

by Einstein in one [8] of his three celebrated papers of 1905 and 

was proven experimentally [9] by Perrin over the next 

decade. [10] Scientists have been fascinated by the implications 

of the stochastic nature of molecular-level motion ever since. 

The random thermal fluctuations experienced by molecules 

dominate mechanical behavior in the molecular world. Even 

the most efficient nanoscale machines are swamped by its 

effect. A typical motor protein consumes ATP fuel at a rate of 

100–1000 molecules every second,which corresponds to a 

maximum possible power output in the region of 10 16 to 

10 17 W per molecule. [11] When compared with the random 

environmental buffeting of approximately 10 8 W experienced 

by molecules in solution at room temperature,it seems 

remarkable that any form of controlled motion is possible. [12] 

When designing molecular machines it is important to 

remember that the presence of Brownian motion is a 

consequence of scale,not of the nature of the surroundings. 

It cannot be avoided by putting a molecular-level structure in 

a near-vacuum,for example. Although there would be few 

random collisions to set such a Brownian particle in motion, 

there would be little viscosity to slow it down. These effects 

always cancel each other out,and as long as a temperature can 

be defined for an object it will undergo Brownian motion 

appropriate to that temperature (which determines the 

kinetic energy of the particle) and only the mean-free path 

between collisions is affected by the concentration of 

particles. In the absence of any other molecules,heat would 

still be transmitted from the hot walls of the container to the 

particle by electromagnetic radiation,with the random 

emission and absorption of the photons producing the 

Brownian motion. In fact,even temperature is not a 

particularly effective modulator of Brownian motion since 

the velocity of the particles depends on the square root of the 

temperature. So to reduce random thermal fluctuations to 

10% of the amount present at room temperature,one would 

have to drop the temperature from 300 K to 3 K. [12,13] It seems 

sensible,therefore,to try to utilize Brownian motion when 

designing molecular machines rather than make structures 

that have to fight against it. Indeed,the question of how to 

(and whether it is even possible to) harness the inherent 

random motion present at small length scales to generate 

motion and do work at larger length scales has vexed 

scientists for some considerable time. 

1.2.1. The Brownian Motion “Thought Machines” 

The laws of thermodynamics govern how systems gain, 

process,and release energy and are central to the use of 

particle motion to do work at any scale. The zeroth law of 

thermodynamics tells us about the nature of equilibrium,the 

first law is concerned with the total energy of a system,while 

the third law sets the limits against which absolute measurements 

can be made. Whenever energy changes hands, 

however,(body to body or form to form) it is the second 

law of thermodynamics which comes into play. This law 

provides the link between the fundamentally reversible laws 

of physics and the clearly irreversible nature of the universe in 

which we exist. Furthermore,it is the second law of 

thermodynamics,with its often counterintuitive consequences,that 

governs many of the important design aspects of how 

to harness Brownian motion to make molecular-level 

machines. Indeed,the design of tiny machines capable of 

doing work was the subject of several celebrated historical 

“thought-machines” intended to test the very nature of the 

second law of thermodynamics. [14–18] 

1.2.1.1. Maxwell’s Demon 


Chemie 

Scottish physicist James Clerk Maxwell played a major 

role (along with Ludwig Boltzmann) in developing the kinetic 

theory of gases,which established the relationship between 

heat and particle motion and gave birth to the concept of 

statistical mechanics. In doing so,Maxwell realized the 

profundity of the statistical nature of the second law of 

thermodynamics which had recently been formulated [19] by 

Rudolf Clausius and William Thomson (later Lord Kelvin). In 

an attempt to illustrate this feature,Maxwell devised the 

thought experiment which has come to be known as 

Maxwell s demon. [14,15,20] 

Angew. Chem. Int. Ed. 2007, 46, 72 – 191 2007 Wiley-VCHVerlag GmbH& Co. KGaA, Weinheim www.angewandte.org 

75

Reviews 

Maxwell envisaged a gas enclosed within a container,to 

and from which no heat or matter could flow. The second law 

of thermodynamics requires that no gradient of heat or 

pressure can spontaneously arise in such a system,as that 

would constitute a reduction in entropy. Maxwell imagined 

the system separated into two sections by a partition 

(Figure 2). Having just proven that the molecules in a gas at 

Figure 2. a) Maxwell’s “temperature demon” in which a gas at uniform temperature is sorted into “hot” 

and “cold” molecules. [15] Particles with energy higher than the average are represented by red dots while 

blue dots represent particles with energies lower than the average. All mechanical operations carried out 

by the demon involve no work—that is, the door is frictionless and it is opened and closed infinitely 

slowly. The depiction of the demon outside the vessel is arbitrary and was not explicitly specified by 

Maxwell. b) A Maxwellian “pressure demon” in which a pressure gradient is established by the door 

being opened only when a particle in the left compartment approaches it. [15c] 

a particular temperature have energies statistically distributed 

about a mean,Maxwell postulated a tiny “being” able to 

detect the velocities of individual molecules and open and 

close a hole in the partition so as to allow molecules moving 

faster than the average to move in one direction (R!L in 

Figure 2) and molecules moving slower than the average to 

move in the other (L!R in Figure 2). All the time,the 

number of particles in each half and the total amount of 

energy in the system remains the same. The result of the 

demon s endeavors being successful would be that one end of 

the system (the “fast” end,L) would become hot and the 

other (the “slow” end,R) cold; thus a temperature gradient is 

set up without doing any work,contrary to the second law of 

thermodynamics. 

After its publication in “Theory of Heat”, [15b] Thomson 

expanded upon Maxwell s idea in a paper [21] read before the 

Royal Society of Edinburgh on 16 February 1874,and 

published a few weeks later in Nature, [22] introducing the 

term “demon” for Maxwell s being. [23] In using this word, 

Thomson apparently did not intend to suggest a malicious 

imp,but rather something more in keeping with the ancient 

Greek roots of the word (more usually daemon) as a 

supernatural being of a nature between gods and humans. 

Indeed,neither Maxwell nor Thomson saw the demon as a 

threat to the second law of thermodynamics,but rather an 

illustration of its limitations—an exposition of its statistical 

nature. This,however,has not been the view of many 

subsequent investigators,who have perceived the demon as 

an attempt to construct a perpetual motion machine driven by 

thermal fluctuations. The term “Maxwell s demon” has come 

to describe all manner of hypothetical constructs designed to 

overcome the second law of thermodynamics by continually 

extracting energy to do work from the thermal bath. [14] 

Maxwell noted that the demon principle could be 

demonstrated in a number of different ways; a “pressure” 

demon,for example,(Figure 2b) could sort particles so that 

more end up in one end of a vessel than the other,which 

required different information to 

operate from the original temperature 

demon (the direction of 

approach of a particle,not its 

speed). 

1.2.1.2. Szilard’s Engine 

Both Maxwell and Thomson 

appreciated that the operation of 

these systems for separating 

Brownian particles appeared to 

rely on the demon s “intelligence” 

as an animate being,but 

did not try to quantify it. Leo 

Szilard made the first attempt to 

mathematically relate the 

demon s intelligence to the thermodynamics 

of the process by 

considering the performance of a 

machine based on the “pressure 

demon”,namely,Szilard s engine 

(Figure 3). [17] Szilard realized that the operations which the 

demon carries out can be reduced to a simple computational 

process. In particular,he recognized the process requires 

measurement of the approach of the particle to gain 

information about its direction and speed,which must be 

remembered and then acted upon. [24] 

1.2.1.3. Smoluchowski’s Trapdoor 

The concept of a purely mechanical Brownian motion 

machine which does not require any intelligent being to 

operate it was first explored by Marian von Smoluchowski 

who imagined the Maxwell system as two gas-containing 

compartments with a spring-loaded trapdoor in place of the 

demon-operated hole (Figure 4a). [16] If the spring is weak 

enough,it might appear that the door could be opened by 

collisions with gas molecules moving in one direction (L!R 

in Figure 4a) but not the other,and so allow transport of 

molecules preferentially in one direction thereby creating a 

pressure gradient between the two compartments. Smoluchowski 

recognized (although could not prove) that if the 

door had no way of dissipating the energy it gains from 

Brownian collisions it would be subject to the same amount of 

random thermal motion as the rest of the system and would 

not then function as the desired one-way valve. 

1.2.1.4. Feynman’s Ratchet and Pawl 


Richard Feynman revisited these ideas in his celebrated 

discussion of a miniature ratchet and pawl—a construct 



Figure 3. Szilard’s engine which utilizes a “pressure demon”. [17] 

a) Initially a single Brownian particle occupies a cylinder with a piston 

at either end. A frictionless partition is put in place to divide the 

container into two compartments (a!b). b) The demon then detects 

the particle and determines in which compartment it resides. c) Using 

this information, the demon is able to move the opposite piston into 

position without meeting any resistance from the particle. d) The 

partition is removed, allowing the “gas” to expand against the piston, 

doing work against any attached load (e). To replenish the energy used 

by the piston and maintain a constant temperature, heat must flow 

into the system. To complete the thermodynamic cycle and reset the 

machine, the demon’s memory of where the particle was must be 

erased (f!a). To fully justify the application of a thermodynamic 

concept such as entropy to a single-particle model, a population of 

Szilard devices is required. The average for the ensemble over each of 

these devices can then be considered to represent the state of the 

system, which is comparable to the time average of a single multiparticle 

system at equilibrium, in a fashion similar to the statistical 

mechanics derivation of thermodynamic quantities. 

designed to illustrate how the irreversible second law of 

thermodynamics arises from the fundamentally reversible 

laws of motion. [18] Feynman s device (Figure 4b) consists of a 

miniature axle with vanes attached to one end,surrounded by 

a gas at temperature T 1. At the other end of the axle is a 

ratchet and pawl system,held at temperature T 2. The question 

posed by the system is whether the random oscillations 

produced by gas molecules bombarding the vanes can be 

rectified by the ratchet and pawl so as to get net motion in one 

direction. Exactly analogous to Smoluchowski s trapdoor, 

Feynman showed that if T 1 = T 2 then the ratchet and pawl 

cannot extract energy from the thermal bath to do work. 

Feynman s major contribution from the perspective of 

molecular machines,however,was to take the analysis one 

stage further: if such a system cannot use thermal energy to do 

work,what is required for it to do so? Feynman showed that 

when the ratchet and pawl are cooler than the vanes (that is, 

T 1 > T 2) the system does indeed rectify thermal motions and 

can do work (Feynman suggested lifting a hypothetical flea 

attached by a thread to the ratchet). [25] Of course,the machine 

now does not threaten the second law of thermodynamics as 

dissipation of heat into the gas reservoir of the ratchet and 

pawl occurs,so the temperature difference must be maintained 

by some external means. Although insulating a 

molecular-sized system from the outside environment is 

Figure 4. a) Smoluchowski’s trapdoor: an “automatic” pressure 

demon (the directionally discriminating behavior is carried out by a 

wholly mechanical device, a trapdoor which is intended to open when 

hit from one direction but not the other). [16] Like the pressure demon 

shown in Figure 2b, Smoluchowski’s trapdoor aims to transport 

particles selectively from the left compartment to the right. However, 

in the absence of a mechanism whereby the trapdoor can dissipate 

energy it will be at thermal equilibrium with its surroundings. This 

means it must spend much of its time open, unable to influence the 

transport of particles. Rarely, it will be closed when a particle 

approaches from the right and will open on collision with a particle 

coming from the left, thus doing its job as intended. Such events are 

balanced, however, by the door snapping shut on a particle from the 

right, pushing it into the left chamber. Overall, the probability of a 

particle moving from left to right is equal to that for moving right to 

left and so the trapdoor cannot accomplish its intended function 

adiabatically. b) Feynman’s ratchet and pawl. [18] It might appear that 

Brownian motion of the gas molecules on the paddle wheel in the 

right-hand compartment can do work by exploiting the asymmetry of 

the teeth on the cog of the ratchet in the left-hand compartment. 

While the spring holds the pawl between the teeth of the cog, it does 

indeed turn selectively in the desired direction. However, when the 

pawl is disengaged, the cog wheel need only randomly rotate a tiny 

amount in the other direction to move back one tooth whereas it must 

rotate randomly a long way to move to the next tooth forward. If the 

paddle wheel and ratchet are at the same temperature (that is, T 1 = T 2) 

these rates cancel out. However, if T 1 ¼6 T 2 then the system will 

directionally rotate, driven solely by the Brownian motion of the gas 

molecules. Part (b) reprinted with permission from Ref. [18]. 

difficult (and temperature gradients cannot be maintained 

over molecular-scale distances,see Section 1.3),what this 

hypothetical construct provides is the first example of a 

plausible mechanism for a molecular motor—whereby the 

random thermal fluctuations characteristic of this size regime 

are not fought against but instead are harnessed and rectified. 

The key ingredient is the external addition of energy to the 

system,not to generate motion but rather to continually or 

cyclically drive the system away from equilibrium,thereby 

maintaining a thermally activated relaxation process that 

directionally biases Brownian motion towards equilibrium. [26] 

This profound idea is the key to the design of molecular-level 

systems that work through controling Brownian motion and is 

expanded upon in Section 1.4. 

1.2.2. Machines That Operate at Low Reynolds Number 


Chemie 

Whilst rectifying Brownian motion may provide the key to 

powering molecular-level machines,it tells us nothing about 

how that power can be used to perform tasks at the nanoscale 

and what tiny mechanical machines can and cannot be 


77

Reviews 

expected to do. The constant presence of Brownian motion is 

not the only distinction between motion at the molecular level 

and in the macroscopic world. In the macroscopic world,the 

equations of motion are governed by inertial terms (dependent 

on mass). Viscous forces (dependent on particle 

dimensions) dampen motion by converting kinetic energy 

into heat,and objects do not move until they are provided 

with specific energy to do so. In a macroscopic machine,this is 

often provided through a directional force when work is done 

to move mechanical components in a particular way. As 

objects become less massive and smaller in dimensions, 

inertial terms decrease in importance and viscosity begins to 

dominate. A parameter which quantifies this effect is the 

Reynolds number R,which is essentially the ratio of inertial 

to viscous forces,and is given by Equation (1) for a particle of 

length a that is moving at velocity v in a medium with viscosity 

h and density 1. [27] 

R ¼ av1 

h 

Size affects the modes of motion long before the nanoscale 

is reached. Even at the mesoscopic level of bacteria 

(length dimensions ca. 10 5 m),viscous forces dominate. At 

the molecular level,the Reynolds number is extremely low 

(except at low pressures in the gas phase or,possibly,in the 

free volume within rigid frameworks in the solid state) and 

the result is that molecules,or their components,cannot be 

given a one-off “push” in the macroscopic sense. Thus, 

momentum is irrelevant. The motion of a molecular-level 

object is determined entirely by the forces acting on it at that 

particular instant—whether they are externally applied 

forces,viscosity,or random thermal perturbations and 

Brownian motion. Furthermore,the tiny masses of nanoscopic 

objects means that the force of gravity is insignificant 

for them. Since the physics which governs mechanical 

dynamic processes in the two size regimes is completely 

different,macroscopic and nanoscale motors require fundamentally 

different mechanisms for controlled transport or 

propulsion. Moreover,the high ratios of surface area to 

volume for molecules mean they are inherently sticky and this 

will have a profound effect on how molecular-sized machines 

are organized and interact with one another. In general terms, 

this analysis leads to a central tenet: while the macroscopic 

machines we encounter in everyday life may provide the 

inspiration for what we might like molecular machines to 

achieve,drawing too close an analogy for how they might do it 

may not be the best design strategy. The “rules of the game” 

at large and small length scales are simply too different. 

[1m,12,13,28] 

1.3. Lessons to Learn from Biology 

Help is at hand,however,because despite all these 

problems,we know that motors and machines at the 

molecular level are conceptually feasible—they are already 

all around us. Nature has developed a working molecular 

nanotechnology that it employs to astonishing effect in 

ð1Þ 


virtually every significant biological process. [11] Appreciating 

in general terms how nature has overcome the issues of scale, 

environment,equilibrium,Brownian motion,and viscosity is 

useful for indicating general traits for the design of synthetic 

molecular machine systems and how they might be used. 

The membranes which encase cells and their organelles 

allow the compartmentalization of cellular processes and 

constituents,thereby maintaining the non-equilibrium distributions 

essential for life. These lipophilic barriers contain a 

diverse range of functionality which facilitate the movement 

of various ionic and polar species through channels,through 

relays or the use of mobile carrier species. [29] A number of 

different mechanisms are employed to power motion from 

one compartment to another. Besides passive diffusion down 

a concentration gradient in the transported species,an 

electrochemical gradient (a transmembrane electrical potential,a 

concentration gradient,or,most commonly,a combination 

of the two) originating from another species can be 

used. Such “gradient pumping” mechanisms move one 

species against its concentration gradient at the expense of 

another gradient. The motion of the two species can be in the 

same direction (symport) or in opposite directions (antiport). 

If the sole power source is an electrical potential,only one 

species crosses the membrane (a uniport mechanism). These 

processes are governed by sophisticated control mechanisms 

which open or close highly selective channels,carriers,and cotransporters 

in response to different stimuli,yet they all 

operate by relaxation down a directional transmembrane 

electrochemical gradient towards the thermodynamic equilibrium 

position. 

The primary concentration gradients which are used to 

power subsequent secondary transport processes are maintained 

by a smaller number of ion pumps. These transmembrane 

mechanical devices convert nondirectional chemical 

reactions (the most abundant family,the ATPases, 

harness the hydrolysis of ATP) into vectorial transport of 

ionic species against an electrochemical gradient. The precise 

mechanisms by which these devices operate are still a subject 

of intense investigation. However,certain principles are 

becoming apparent. In particular,changes in the binding 

affinity at selective sites in the transmembrane region of the 

pump must be coupled to conformational changes which also 

modulate access to these sites from either side of the 

membrane so that only motion in the desired direction is 

achieved. [30] 

A recent series of structures has outlined how just such a 

mechanism operates in the sarcoplasmic reticulum Ca 2+ - 

ATPase pump. [31] Calcium ions bind to two high affinity sites 

which are open to the cytoplasm (B,Figure 5). Phosphorylation 

of the enzyme by ATP then results in a conformational 

change which shuts off access from either side (ratcheting [32] ). 

Release of ADP is concomitant with a further conformational 

change which opens up access to the lumen side and disrupts 

the Ca 2+ -binding residues (A,Figure 5). The calcium ions are 

released (escapement [32] ) and swapped for protons which are 

subsequently occluded from the lumen by binding of a water 

molecule. Release of phosphate occurs with regeneration of 

the starting state,once again making the high-affinity Ca 2+ - 

binding sites accessible to the cytoplasm. Similar mechanisms 



Figure 5. Crystal structures of the calcium-binding region in 

Ca 2+ -ATPase in both low Ca 2+ -affinity (A) and high Ca 2+ -affinity (B) 

conformations. [31] Calcium ions are shown in green, and the numbers 

correspond to specific protein helices. The crystal structure pictures 

are reprinted with permission from Ref. [30b]. 

are thought to be responsible for the operation of the other 

members in the ATPase family. 

The pumping of protons across the energy-transducing 

membranes of mitochondria,chloroplasts,and photosynthetic 

and respiratory bacteria is a particularly important process as 

it generates the protonmotive force necessary to operate ATP 

synthase (and also directly or indirectly powers the secondary 

transport of other species across these membranes). The ways 

in which nature achieves this pumping function are surprisingly 

diverse (by contrast,ATP synthase is highly conserved 

across organisms). [33] In most examples,charge-separated 

states and electron-transfer processes are used to generate 

transmembrane electric potentials. Overall,therefore,a 

directional electrochemical driving force is set up to drive 

the translocation of protons,somewhat similar to the gradient 

pumping secondary transport processes discussed above. 

Proton transport is concomitant with the resetting of the 

redox centers in processes often termed “redox loops” or 

“Mitchell loops”. [34] Only in the case of bacteriorhodopsin 

(the photosynthetic center of certain purple bacteria) does it 

appear that light energy is directly converted into protonmotive 

force by a purely conformational pumping mechanism. [35] 

Again,the details of this process are not yet fully understood, 

but the correlation of conformational changes that control the 

direction in which the protons can move with changes in the 

affinity (that is,pK a) of binding sites are likely to be 

involved. [36] 

Nature also uses molecular machines to transport objects 

around within cells (for example,kinesin or dynein); to move 

whole organisms or their parts (for example,myosin or the 

bacterial flagellar motor); to process DNA and RNA (for 

example,helicases or polymerases); to convert protonmotive 

force into the synthesis of ATP (ATP synthase); and for may 

other functions besides. In these cases,too,much has been 

learnt about the various ways in which they perform their 

remarkable tasks,yet much remains to be discovered about 

each before the precise mechanisms can be elucidated. [11] 

Accordingly,we can see that there are many general and 

fundamental differences between biological molecular 

machines and the man-made machines of the macroscopic 

world. Listed below are what appear to us to be the most 


Chemie 

significant aspects of biological machines to bear in mind 

when considering synthetic molecular machine design. 

1) Biological machines are soft,not rigid. 

2) Biological systems operate at near-ambient temperatures 

(heat is dissipated almost instantaneously at small length 

scales so they cannot exploit temperature gradients). 

3) Biological motors utilize chemical energy,in the form of 

covalent-bond breaking/formation of high-energy compounds 

such as ATP,NADH,and NADPH or concentration 

gradients. 

4) Biomachines operate in solution,or at surfaces,under 

conditions of intrinsically high viscosity. 

5) Nature utilizes—rather than opposes—Brownian 

motion. Biomolecular machines need not use chemical 

energy to initiate movement—their components are 

constantly in motion—rather,they function by manipulating 

(ratcheting) that movement. Furthermore,constant 

thermal motion and small “reaction vessels” (cells 

and their organelles) ensure that the mixing of biological 

machines,their substrates,and their fuel is extremely 

rapid,in spite of the high viscosity they experience. 

6) The viscous environment and constant thermal motion 

mean that biological machines have no use for smooth, 

low-friction surfaces. Genuinely smooth features are not 

possible on the molecular scale,of course,since the 

machine-component dimensions are close to the dimensions 

of the intrinsic unit of matter—the atom. 

7) Biomotors and other mobile machines utilize architectures 

(for example,tracks) which serve to restrict most of 

the degrees of freedom of the machine components and/ 

or the substrate(s) they act upon. The molecular machine 

and the substrate(s) it is acting upon remain kinetically 

associated during the operation of the machine. For 

example,kinesin only functions as it “walks” processively 

down a microtubule,not by simply binding to the 

microtubule at different places (that is,not by completely 

detaching,exchanging with the bulk,and rebinding). 

Similarly,pumps work by internally compartmentalizing 

ions so that they cannot exchange with others outwith the 

machine. 

8) The operation and structure of biological machines are 

governed by noncovalent interactions (intramolecular 

and intermolecular),many of which exploit the aqueous 

environment in which the machines assemble and 

operate. 

9) Biological machines are made by combinations of multiple 

parallel synthesis and self-assembly processes utilizing 

a relatively small range of building blocks: amino 

acids nucleic acids,lipids,and saccharides. 

10) Living organisms intrinsically and necessarily function 

far from equilibrium—a state maintained by the compartmentalization 

of processes into cells,vesicles,and 

organelles. 

We should also remember,however,that the mechanisms 

and function of biomolecular machines are restricted by 

evolutionary constraints. Over billions of years,evolution has 

led to machines of a complexity not yet possible through 

rational design,but it intrinsically proceeds through small 


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iterations and tends to retain the first successful solution 

arrived at for each problem. The human molecular-machine 

designer has at his or her disposal a much larger chemical 

toolbox,a wider range of possible operating conditions,and, 

as we shall see,a design approach that favors innovation. 

Furthermore,whilst an appreciation of the characteristics 

of biological machines can give us broad clues about how to 

make molecular-level devices that exploit mechanical motion, 

we understand few of the precise details of how their designs 

work. How does an inherently mechanically directionless 

chemical reaction—the conversion of ATP into ADP—drive 

the directional motion of calcium ions by Ca 2+ -ATPase? 

What is the detailed nature of the conformational changes 

which can set-up or disrupt the highly selective binding sites? 

Why exactly do the movements of the individual peptide 

subunits that cause this to happen occur in that particular 

sequence? What are the details of the pathways connecting 

the binding sites with the outside? What is the role of the 

kinetics and thermodynamics of each amino acid in this 

mechanism? In fact,biological motors and machines are so 

complex that studying simple synthetic chemical systems may 

help in the understanding of exactly how they work. Likewise, 

fully understanding the biological systems can only aid the 

design of sophisticated artificial systems. At present,however, 

much of the most detailed information for devising the basic 

mechanisms for synthetic molecular machines comes not from 

biology,but from non-equilibrium statistical mechanics. 

1.4. Lessons To Learn from Physics, Mathematics, and Statistical 

Mechanics 

1.4.1. Breaking Detailed Balance 

The Principle of detailed balance [37] states that at equilibrium,transitions 

between any two states take place in either 

direction at the same rate so that no net flux is generated. This 

rules out the maintenance of equilibria by cyclic processes 

such as A!B!C!A rather than AÐB + BÐC + CÐA [12] 

and is a formal indication that machines such as Smoluchowski 

s trapdoor and Feynman s ratchet and pawl cannot 

operate adiabatically. However,in an out-of-equilibrium 

system (for example,if T 1 ¼6 T 2 for the Feynman ratchet and 

pawl),“detailed balance” is broken,and net work can be done 

by the fluxional exchange process as the system moves 

spontaneously towards equilibrium. 

To understand the mechanisms by which mechanical 

machines can operate on length scales at which Brownian 

motion occurs it is useful to appreciate precisely why work 

can be done by a random exchange process between two 

states only while detailed balance is broken. A simple analogy 

helps illustrate why detailed balance holds in a fluxionally 

exchanging system at equilibrium and the requirements 

necessary to break it. Consider a pair of scales with many 

ants running randomly between the two sides,the scales will 

be statistically balanced (but not necessarily horizontal,that 

only occurs if the pivot of the scale is positioned in the middle) 

and remain more or less steady at a stable angle. Even if a 

barrier is suddenly placed between the scales,thus stopping 

the two sides being in equilibrium,they remain balanced. 


However,if ants are added to one side or the other the scales 

become unbalanced and will tip accordingly. If the barrier is 

removed,the ants (assuming they can overcome the effect of 

gravity!) resume scurrying between the two sides and 

eventually equilibrium—and balance—will be restored. 

Note that even if we start without the barrier in place,if 

ants are suddenly added to one side balance will be broken for 

some time—and the scale will tip—until the roaming ants 

establish equilibrium and balance is restored. The breaking of 

balance allows a task to be performed as the exchanging 

system returns toward equilibrium. The net displacement that 

arises as the scales tip over (or as they right themselves) could 

be used to lift a feather to which the scale was attached. 

Breaking detailed balance is the key to doing work with a 

machine that operates at length scales on which Brownian 

motion occurs. 

During the past decade,a number of remarkable theoretical 

formalisms have been developed in mathematics 

(particularly game theory) and non-equilibrium statistical 

physics that explain how the directional transport of Brownian 

particles over periodic potential-energy surfaces can 

occur from unbiased periodic or stochastic perturbations of 

the system. [38,39] Underlying each of these Brownian ratchet or 

motor mechanisms are three components: [39b] 1) a randomizing 

element; [40] 2) an energy input to avoid falling foul of the 

second law of thermodynamics; and 3) asymmetry in the 

energy or information potential in the dimension in which the 

motion occurs. [41] It is now widely accepted that ratchet 

mechanisms have a central role in explaining the operation of 

biological motor proteins. [42,43] They have also been successfully 

used to develop transport and separation devices for 

mesoscopic particles and macromolecules,microfluidic 

pumping,as well as quantum and electronic applications. [43,44] 

For molecular-level motors and other machines,the necessary 

randomizing element can be Brownian motion of the 

substrate or the machine components. The other two requirements 

(energy and anisotropy) can be supplied in different 

ways according to the type of fluctuation-driven transport 

mechanism. 

1.4.2. Fluctuation-Driven Transport Mechanisms 

Many different possible types of theoretical fluctuationdriven 

(“Brownian ratchet”) mechanisms have been proposed,including 

flashing ratchets,tilting ratchets,Seebeck 

ratchets,drift ratchets,Hamiltonian ratchets,temperature 

ratchets,and entropic ratchets. [39] They can be classified and 

grouped together in many different (not always mutually 

exclusive) ways,and mechanisms that might be indistinguishable 

in chemical terms can be differentiated because of the 

nature of the physics involved. Whilst it is not clear (at least to 

us!) how some of the theoretical mechanisms could be 

applied to molecular structures,many offer clear design 

opportunities for the synthetic chemist. The details of the 

various mechanisms have been discussed extensively in the 

physics literature,so we will limit our discussion here to some 

specific variations which appear particularly well-suited for 

chemical systems. We choose to distinguish between two 

overarching classes of mechanism: energy ratchets,which fall 



into two basic types—pulsating ratchets and tilting ratchets— 

and are the subject of a recent major review by Reimann, [39f] 

and information ratchets,which are much less common in the 

physics literature,but have been discussed by Parrondo, 

Astumian,and others. [39h,42b,45] Both energy ratchets and 

information ratchets bias the movement of a Brownian 

substrate. [46] However,we will also show (Sections 1.4.3 and 

4.4) that they offer clues for how to go beyond a simple switch 

with a chemical machine to enable tasks to be performed 

through the non-equilibrium control of conformational and 

co-conformational changes within molecular structures. 

[39f ] 

1.4.2.1. Pulsating Ratchets 

Pulsating ratchets are a general category of energy ratchet 

in which potential-energy minima and maxima are varied in a 

periodic or stochastic fashion,independent of the position of 

the particle on the potential-energy surface. In its simplest 

form this can be considered as an asymmetric sawtooth 

potential being repetitively turned on and off faster than 

Brownian particles can diffuse over more than a small fraction 

of the potential energy surface (an “on–off” ratchet, 

Figure 6). The result is net directional transport of the 

particles across the surface (left to right in Figure 6). 

More general than the special case of an on–off ratchet, 

any asymmetric periodic potential may be regularly or 

stochastically varied to give a ratchet effect (such mechanisms 

are generally termed “fluctuating potential” ratchets). As 

with the simple on–off ratchet,most commonly encountered 

examples involve switching between two different potentials 

and are therefore often termed “flashing” ratchets. A classic 

example,which has particular relevance for explaining a 

Figure 6. An example of a pulsating ratchet mechanism—an on–off 

ratchet. [39f] a) The Brownian particles start out in energy minima on the 

potential-energy surface with the energy barriers @ k BT. b) The potential 

is turned off so that free Brownian motion powered diffusion is 

allowed to occur for a short time period (much less than required to 

reach global equilibrium). c) On turning the potential back on again, 

the asymmetry of the potential means that the particles have a greater 

probability of being trapped in the adjacent well to the right rather 

than the adjacent well to the left. Note this step involves raising the 

energy of the particles. d) Relaxation to the local energy minima 

(during which heat is emitted) leads to the average position of the 

particles moving to the right. Repeating steps (b)–(d) progressively 

moves the Brownian particles further and further to the right. 

number of biological processes [42b] as well as being the basis 

for a [2]catenane rotary motor (see Section 4.6.3),is illustrated 

in Figure 7. It consists in physical terms of an 

asymmetric potential-energy surface (comprising a periodic 

Figure 7. Another example of a pulsating ratchet mechanism—a flashing 

ratchet. [42b] For details of its operation, see the text. 


Chemie 

series of two different minima and two different maxima) 

along which a Brownian particle is directionally transported 

by sequentially raising and lowering each set of minima and 

maxima. The particle starts in a green or orange well 

(Figure 7a or c). Raising that energy minimum while lowering 

those in adjacent wells provides the impetus for the particle to 

change position by Brownian motion (Figure 7b!7cor7d! 

7e). By simultaneously (or beforehand) changing the relative 

heights of the energy barrier to the next energy well,the 

kinetics of the Brownian motion in each direction are 

different and the particle is transported from left to right. 

Note that the position of the particle does not influence the 

sequence in which (or when,or if) the energy minima and 

maxima are changed. Furthermore,the switching of the 


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potential does not have to be regular. As long as the two sets 

of energy minima and maxima are repetitively switched in the 

same order,the particle will tend to be transported from left 

to right in Figure 7,even though occasionally it may move 

over a barrier in the wrong direction. 

The basic pulsating ratchet requirements can also be 

realized in another way. A potential such as that shown in 

Figure 7a can be given a directional drift velocity. Such 

systems are often termed “traveling potential” ratchets. This 

principle is essentially the same as macroscopic devices such 

as Archimedes screw,yet in the presence of thermal 

fluctuations these systems exhibit Brownian ratchet characteristics 

and are closely related to tilting the potential in one 

direction (as discussed in Section 1.4.2.2). Clearly,however, 

an asymmetric potential is not absolutely required,nor in fact 

are thermal fluctuations; imagine,for example,a particle 

“surfing” on a traveling wave on the surface of a liquid. This 

category of mechanism is at the boundary between fluctuation-driven 

transport and transport as a result of potential 

gradients,with the precise location on this continuum 

dependent on the importance of thermal fluctuations and 

spatial asymmetry under the conditions chosen. In terms of 

chemical systems,the traveling-potential mechanism has most 

relevance for the field-driven processes discussed in Section 5 

and the self-propulsion mechanisms of Section 6,while in 

Section 7 we shall discuss some situations in which the 

balance between random fluctuations and external directional 

driving force is shifted strongly towards the latter. The 

traveling motion does not have to be continuous,but rather 

may take place in discrete steps. Furthermore,arranging a 

continuously traveling potential to “jump” distances which 

are multiples of its period,at random or regular intervals,can 

be used to escape from the inherent directionality of the 

traveling-wave scheme and it has been shown that the ratchet 

dynamics are essentially unaffected. In the limiting situation, 

this can be reduced to dichotomous switching between two 

spatially shifted potentials which are otherwise identical, 

which is very similar to a rocking ratchet (see Section 1.4.2.2) 

and is also relevant to the unidirectional motors discussed in 

Section 2.2. 

[39f ] 

1.4.2.2. Tilting Ratchets 

In this category,the underlying intrinsic potential remains 

unchanged and the detailed balance is broken by application 

of an unbiased driving force to the Brownian particle. Perhaps 

the most apparent unbiased driving force is heat,and ratchet 

mechanisms based on periodic or stochastic temperature 

variations are generally termed “temperature” or “diffusion” 

ratchets. In its simplest form (Figure 8) this mechanism is very 

similar to the on–off ratchet. Initially the thermal energy is 

low so that the particles cannot readily cross the energy 

barriers. A sudden increase in temperature can be applied so 

that k BT is much greater that the potential amplitude causing 

the particles to diffuse as if over a virtually flat potentialenergy 

surface (Figure 8b). Returning to the original,lower, 

temperature (Figure 8c) is equivalent to turning the potential 

back on in Figure 6c and more particles will have moved to 

the next well to the right than to the left. Under this scheme, 


Figure 8. A temperature (or diffusion) ratchet. [39f] a) The Brownian 

particles start out in energy minima on the potential-energy surface 

with the energy barriers @ k BT 1. b) The temperature is increased so 

that the height of the barriers is ! k BT 2 and effectively free diffusion is 

allowed to occur for a short time period (much less than required to 

reach global equilibrium). c) The temperature is lowered to T 1 once 

more, and the asymmetry of the potential means that each particle is 

statistically more likely to be captured by the adjacent well to the right 

rather than the well to the left. d) Relaxation to the local energy 

minimum (during which heat is emitted) leads to the average position 

of the particles moving to the right. Repeating steps (b)–(d), progressively 

moves the Brownian particles further and further to the right. 

Note the similarities between this mechanism and that of the on–off 

ratchet shown in Figure 6. 

therefore,it seems that applying temperature variations to 

any process which involves an asymmetric potential-energy 

surface could result in a ratchet effect. [47] In chemical terms, 

this means that the rotation of a chiral group around a 

covalent bond can,at least in principle,be made unidirectional 

in such a manner. This concept is explored further in 

relation to a molecular ratchet system in Section 2.1.2. 

An unbiased driving force can also be achieved by 

applying a directional force in a periodic manner so that, 

over time,the bias averages to zero,thus generating a 

“rocking” ratchet. The simplest form of this is shown in 

Figure 9. Periodic application (to the left and then right) of a 

driving force that allows the particle to surmount the barriers 

(for example,by applying an external field if the particle is 

charged) results in transport. Motion over the steep barrier is 

again most likely as it involves the shortest distance. Such a 

mechanism is physically equivalent to tilting the ratchet 

potential in one direction then the other. Of course,if the 

driving force is strong enough and is constantly applied in one 

direction or the other,thermal fluctuations are not necessary, 

which would then correspond to a power stroke. 

Analogues of a rocking ratchet in which the applied 

driving force is a form of stochastic noise are known as 

“fluctuating force” ratchets (in certain cases,also “correlation” 

ratchets). Finally,a tilting ratchet can be achieved in a 

symmetric potential if the perturbation itself results in spatial 

asymmetry (becoming very similar to the travelling-potential 

models in Section 1.4.2.1). This may be rather clear for the 



Figure 9. A rocking ratchet. [39f] a) The Brownian particles start out in 

energy minima on the potential-energy surface with the energy barriers 

@ k BT. b) A directional force is applied to the left. c) An equal and 

opposite directional force is applied to the right. d) Removal of the 

force and relaxation to the local energy minimum leads to the average 

position of the particles moving to the right. Repeating steps (b)–(d) 

progressively moves the Brownian particles further and further to the 

right. 

periodic force cases (imagine applying the electric field 

discussed above for longer in one direction than the other), 

but is less so for stochastic driving forces. In general,these 

mechanisms are known as “asymmetrically tilting” ratchets. 

[39h,42b, 45] 

1.4.2.3. Information Ratchets 

In the pulsating and tilting types of energy ratchet 

mechanisms,perturbations of the potential-energy surface— 

or of the particle s interaction with it—are applied globally 

and independent of the particle s position,while the periodicity 

of the potential is unchanged. Information ratchets 

(Figure 10) transport a Brownian particle by changing the 

effective kinetic barriers to Brownian motion depending on 

the position of the particle on the surface. In other words,the 

heights of the maxima on the potential-energy surface change 

according to the location of the particle (this requires 

information to be transferred from the particle to the surface) 

whereas the potential-energy minima do not necessarily need 

to change at all. This switching does not require raising the 

potential energy of the particle at any stage,rather the motion 

can be powered with energy taken entirely from the thermal 

bath by using information about the position of the particle. 

This is directly analogous to the mechanism required of 

Maxwell s pressure demon (Figure 2b,Section 1.2.1.1),but 

does not break the second law of thermodynamics as the 

required information transfer (actually,information erasure 

[48] ) has an intrinsic energy cost that has to be met 

externally. 

Figure 10. A type of information ratchet mechanism for transport of a 

Brownian particle along a potential-energy surface. [39h, 42b, 45] Dotted 

arrows indicate the transfer of information that signals the position of 

the particle. If the signal is distance-dependent—say, energy transfer 

from an excited state which causes lowering of an energy barrier— 

then the asymmetry in the particle’s position between two barriers 

provides the “information” which transports the particle directionally 

along the potential energy surface. 


Chemie 

It appears to us that information-ratchet mechanisms of 

relevance to chemical systems can arise in at least three ways: 

1) a localized change to the intrinsic potential-energy surface 

depending on the position of the particle (Figure 10); 2) a 

position-dependent change in the state of the particle which 

alters its interaction with the potential-energy surface at that 

point; or 3) switching between two different intrinsic periodic 

potentials according to the position of the particle. [39h,49] An 

example of the first of these types,in which the system 

responds to the “information” from the particle by lowering 

the energy barrier to the right-hand side (and only to the 

right-hand side) of the particle,is shown in Figure 10. 

The particle starts in one of the identical-minima energy 

wells (Figure 10a). The position of the particle lowers the 

kinetic barrier for passage to the adjacent right-hand well and 

it moves there by Brownian motion (10 b!10 c). At this point 

it can sample two energy wells by Brownian motion,and a 

random reinstatement of the barrier has a 50% chance of 

returning the particle to its starting position and a 50% 

chance of trapping it in the newly accessed well to the right 


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(Figure 10 d,of course a more efficient mechanism could be 

envisaged in which a second information transfer signals the 

occupation of the right-hand well and raises the barrier at this 

point only). The particle can no longer go back to the starting 

well but is now allowed access to the next well further to the 

right. Even though no enthalpic driving force ever exists for 

the particle to move from left to right,it is inevitably 

transported in that direction through such a mechanism. The 

potential-energy surface in Figure 10 is asymmetric,but this is 

not necessary if some other means can be devised of 

communicating the position of the particle (and therefore 

breaking spatial inversion symmetry). 

Both energy ratchets and information ratchets could 

provide valid operating mechanisms for synthetic molecularlevel 

machines. Furthermore,hybrid mechanisms appear to 

be possible. For example,by using asymmetry in the 

Brownian particle (for example,a cyclodextrin) rather than 

in the potential-energy surface to induce directionality of 

motion. [50] Indeed,it seems that the realization of functioning 

synthetic chemical machine systems could have as much to 

offer theoretical non-equilibrium statistical physics as the 

other way around. 

1.4.3. From Motors to Driving Non-equilibrium Changes in 

Chemical Systems 

Theoretical fluctuation-driven transport mechanisms have 

generally been considered in terms of either two-minima 

potential-energy surfaces or an infinitely repeating potentialenergy 

surface. The former can be the basis for molecular 

switches,while the latter can be employed directly as designs 

for molecular-level motors. [51] What other general ideas can 

we glean from how these systems work from the viewpoint of 

designing other types of synthetic molecular-level machines 

that exploit Brownian motion? 

1) Asymmetry in some part of the fluctuation-driven transport 

cycle is necessary to ensure that time-reversal 

symmetry is broken,which means that the particles 

undergo nonreciprocal motion during the operating 

cycle,thus generating a directional flux. This means that 

the particles are not subjected to the opposite of the initial 

transport process as the potential is being reset to begin 

another cycle. 

2) In all these mechanisms (for example,Figures 6–10) we 

can see that the particles are always under the influence of 

the potential-energy surfaces responsible for transporting 

them. Even in the on–off ratchet (Figure 6),the sawtooth 

potential can only be switched off for a short time. If it 

were switched off for long enough for the particles to 

reach an equilibrium distribution over the surface,then 

the mechanism would not be able to directionally transport 

the particles progressively,it could only switch 

between one (average) equilibrium distribution and 

another. In other words,for a machine to operate by 

these types of mechanisms which manipulate non-equilibrium 

states,Brownian substrates must remain kinetically 

associated with the machine throughout its operation—not 

necessarily in physical contact but rather not 

able to exchange with substrates in the bulk,which are not 


under the influence of the machine. (This is why we rule 

out host–guest complexes that are under thermodynamic 

control acting as such machines (Section 1.1).) Exchanging 

with the bulk while entering the machine at one end 

and when leaving at the other is allowed when the two 

bulk regions are themselves otherwise separated (for 

example,a transmembrane pump). 

3) The particles in all fluctuation-driven transport mechanisms 

can be considered to be “compartmentalized”,in 

that at any moment the particles are free to move only 

over a localized area (which continually changes during 

the operating cycle of the machine). The compartment 

boundaries are not necessarily physical ones; when the 

sawtooth potential in the on–off ratchet in Figure 6 is 

switched off,it is the short time before the potential is reapplied 

that prevents the particles coming to global 

equilibrium over the surface. 

4) It is the manipulation of the Brownian particles in terms of 

which and when compartments are “linked” (able to 

exchange particles) and the statistical balance of the 

populations of linked compartments with respect to the 

potential-energy surface (in the case of energy ratchets) or 

information (in the case of information ratchets) that 

enables the transport mechanism to function. 

5) Energy ratchets (in which the Brownian substrate is 

passive) have been the most widely considered fluctuation-driven 

transport mechanisms in the physics literature. 

However,the components of chemical systems are not 

always passive. For molecular structures it seems likely 

that information ratchets (where the position of the 

Brownian particle or fragment affects the potentialenergy 

surface) will also prove of great utility and 

importance. 

6) Fluctuation-driven transport mechanisms are often considered 

in terms of charged particles,with electric fields 

being applied,typically to generate an infinitely repeating 

potential-energy surface. In chemical systems,noncovalent 

interactions and binding interactions can provide the 

necessary changing potential-energy surface,which can be 

of limited length and not uniform,with the Brownian 

substrate being either another ion or molecule or it could 

be another fragment of the same molecule. [52] 

7) Although the mechanisms for fluctuation-driven transport 

have been developed to direct the flow of particles in a given 

direction, we can consider applying the same sorts of ideas 

to generate other sorts of non-equilibriumdistributions 

within molecular-level structures. It should be possible to 

design molecular-level machine systems that are neither 

switches nor motors by utilizing small numbers of real or 

virtual “compartments” within a molecular (or supramolecular) 

structure that can be “linked” (and 

“unlinked”) and “balanced” (and “unbalanced”) in particular 

ways,perhaps by using Boolean logic operations, 

and addressed through orthogonal inputs to perform some 

function (see,for example,the “sorting and separating” 

machine suggested in Section 4.4). Fluctuation-driven 

transport mechanisms are illustrative of the general 

principles through which non-equilibrium distributions 

of supramolecular,molecular,and submolecular struc- 



tures can be created,controlled,ordered,and manipulated 

by inputs of energy. 

These are the principles used to develop the concepts for 

the compartmentalized molecular machines described in 

Section 4.4. However,it is interesting to consider that they 

are equally relevant for the design of interacting chemical 

reaction cascades and catalytic cycles that operate far from 

equilibrium. 

If biology,mathematics,and physics provide the inspiration 

and strategies for controlling molecular-level motion,it is 

through chemistry that artificial molecular-level machine 

mechanisms must be designed,constructed,and made to 

work. The minimum requirements for such systems must be 

the restriction of the 3D motion of the machine components 

and/or the substrate as well as a change in their relative 

positions induced by an input of energy. Ways of achieving 

control over conformational dynamics involving single bonds 

and double bonds,as well as over co-conformational dynamics 

in kinetically stable supramolecular and mechanically 

bonded systems,are discussed in Sections 2–7. 

2. Controlling Motion in Covalently Bonded 

Molecular Systems 

2.1. Controlling Conformational Changes 

2.1.1. Correlated Motion through Nonbonded Interactions 

In compounds where two or more bulky planar substituents 

are geminally or vicinally connected,the congested steric 

environment often demands a helical ground state where all 

the rings are tilted in the same direction,thus generating a 

structure reminiscent of the macroscopic screw propellers 

found on aeroplanes and boats. The lowest energy rotational 

processes in such systems generally involve correlated motion 

of the planar “blades” (known as “cogwheeling”),and their 

investigation played an important early role in illustrating 

how motion can be controlled by molecular structure. [53] 

Inspired by the work of Ōki on the high threefold torsional 

barrier in bridgehead-substituted triptycenes, [54] the research 

groups of Mislow and Iwamura independently replaced the 

twofold aryl “rotators” [1k] of molecular propellers with 9triptycyl 

units,thereby creating so-called “molecular 

gears”. [53c,55–57] In these systems,the blades of each triptycyl 

group are tightly intermeshed,so that correlated disrotatory 

motion is strongly preferred. Such “dynamic gearing” mirrors 

the operation of a macroscopic bevel gear, [58] with correlated 

conrotation or uncorrelated rotation amounting to gear 

slippage. This threshold mechanism maintains the relationship 

between torsional angles of the two rotators. Changing 

this relationship can only occur by one of the higher energy 

rotational processes,so that stereoisomerism arises when at 

least one blade of each triptycyl is differentiable (illustrated 

for 1,Scheme 1a). [59] As the isomers differ in the phase 

relationship between the substituted rings,the term “phase 

isomers” was coined for this subset of residual isomerism. [56c] 

Experimental and theoretical studies confirm that the correlated 

disrotation is generally favored over other torsional 


Chemie 

Scheme 1. a) The three residual diastereoisomers of molecular gear 

1. [57b] Correlated disrotation maintains the phase relationship between 

the labeled blades (shown here in red) for each isomer. Interconversion 

between isomers (“gear slippage”) requires correlated conrotation 

or uncorrelated rotation. b) Molecular gear train 2. [60] c) Vinyl molecular 

gear 3 (shown as the racemic residual diastereomer); [61] a 

molecular gear 4 with a 2:3 gearing ratio; [62j] and a molecular gear 5 

based on revolution around a metallocene and with a 3:4 gearing 

ratio. [63] The arrows show correlated motions but are not meant to 

imply intrinsic directionality. 

processes by 30–40 kcal mol 1 

in these systems,largely 

because of the remarkable ease of the disrotary motion 

(DG ° = ca. 1–2 kcalmol 1 ). This result actually represents 

stricter selectivity than occurs for the selection rules that 

govern correlated torsions under orbital symmetry control 

(see Section 2.1.5). 

Iwamura and co-workers successfully extended the 

dynamic gearing concept to multiple gear systems in which 

each adjacent pair must disrotate,so that the behavior of the 

outermost rotators is dependent of the number of linkages in 

the chain. In 2 therefore (Scheme 1b),despite the large 

number of possible conformations and increased flexibility of 

the chain,the two outer triptycyl units conrotate and the 

phase relationship of the two chlorine labels is strictly 

maintained in both phase isomers. [60] 

Dynamic gearing has also been realized in vicinally linked 

triptycyl rotors,such as 3 (Scheme 1c), [61] and in systems with 

gearing ratios other than 3:3,for example,2:3 (4), [62] and 3:4 

(5). [63] Although the low-energy dynamic processes observed 

in 5 could not be unequivocally shown to be correlated,this 


85

Reviews 

system is one of the first 

molecular structures in 

which the facile rotation 

of p fragments in metallocenes 

was utilized,thus 

prompting analogy with a 

ball bearing. [64] 

The same comparison 

can be applied to a more 

recent series of trinuclear 

sandwich complexes in 

which multiple correlated 

motions have been demonstrated. 

[65] Each silver 

cation in [Ag 3(6) 2] has a 

linear coordination geometry,bound 

to one nitrogen 

donor from each trismonodentate 

disk-shaped 

ligand (red)—the resulting 

complex is helical, 

with all the thiazolyl 

rings tilted in the same 

direction (Figure 11b). 

Random helix inversion 

is a low-energy process, 

which occurs through a 

nondissociative “flip” 

motion whereby rotation 

of the heteroaromatic 

rings so that they point 

in the opposite direction 

is accompanied by a 1208 

relative rotation of the two large disks (illustrated for 

[Ag 3(6)(7)] in Figure 11 c). [65a] In the heteroleptic analogue 

[Ag 3(6)(7)],a similar coordination geometry is adopted so 

that only every alternate thiazolyl ring in the hexakismonodentate 

disk ligand (blue) is bound at any one time. 

The “flip” helix reversal,during which the ligand and metal 

partners do not change,can clearly still occur. Ligand 

exchange is also rapid,however,and most likely occurs via 

the trigonal transition state illustrated in Figure 11 c. The 

overall result is a correlated rotation of the heteroaromatic 

rings together with a 608 relative rotation of the two disks. If a 

ligand exchange and a flip step occur concurrently,the sense 

of rotation in each step is opposite,so that overall a 608 

relative rotation of the disk-shaped ligands occurs. [65b,c] 

While all these and other [66] related studies clearly 

demonstrate the role steric interactions can play,at equilibrium 

the submolecular motions are nondirectional even 

within a partial rotational event. Simply restricting the 

thermal rotary motion of one unit by a larger blocking 

group or by the similarly random motion of another unit 

cannot,in itself,lead to directionality. A molecular machine 

requires some form of external modulation over the dynamic 

processes to drive the system away from equilibrium and 

break detailed balance. 


Figure 11. a) Chemical structure of tris-monodentate disk-shaped ligand 6 and hexakis-monodentate ligand 

7. [65] b) Schematic representation of complex [Ag 3(6) 2] arbitrarily shown as its M-helical enantiomer. 

c) Description of the two correlated rotation processes occurring in [Ag 3(6)(7)]. The direction of rotation for 

an M!P transition through ligand exchange is opposite to that for the potentially subsequent P!M’ 

transition by the nondissociative flip mechanism. Schematic representations reprinted with permission from 

Refs. [65a,c]. 

2.1.2. Stimuli-Induced Conformational Control around a Single 

Covalent Bond 

As a first step towards achieving controlled and externally 

initiated rotation around C C single bonds,Kelly and coworkers 

combined triptycene structures with a molecularrecognition 

event. [67] In the resulting “molecular brake” 8 

Scheme 2. “Molecular brakes” induced by a) metal-ion binding [68] and 

b) redox chemistry. [70] EDTA = ethylenediaminetetraacetate, mCPBA = 

meta-chloroperbenzoic acid. 



(Scheme 2a), [68] free rotation of a triptycyl group is halted by 

the conformational change brought about by complexation of 

the appended bipyridyl unit with Hg 2+ ions,thus effectively 

putting a “stick” in the “spokes”. [69] A similar “braking effect” 

has been demonstrated by using redox chemistry and Narylindolinone 

9 (Scheme 2b); both oxidized forms of the 

sulfur side chain exhibit markedly increased barriers to 

rotation around the N aryl bond (see 

also 45,Scheme 21). [70,71] 

Kelly et al. next extended their 

investigation of restricted Brownian 

rotary motion to a molecular realization 

(10) of the Feynman adiabatic 

ratchet and pawl, [72] in which a helicene 

plays the role of the pawl in attempting 

to direct the rotation of the attached 

triptycene “cog wheel” in one direction 

as a result of the chiral helical structure. 

Although the calculated energetics for 

rotation showed an asymmetric potential 

energy profile (Figure 12 b), 

NMR experiments confirmed that rotation 

occurred with equal frequency in 

both directions. This result is,of course, 

in line with the conclusions of the 

Feynman thought experiment (Section 

1.2.1.4). [73] The rate of a molecular 

transformation (clockwise and anticlockwise 

rotation in 10 included) 

depends on the energy of the transition 

state (and the temperature),not the 

shape of the energy barrier: state 

functions such as enthalpy and free 

energy do not depend on a system s 

history. [74] Thus,although rotation in 10 

follows an asymmetric potential-energy surface,the principle 

of detailed balance at equilibrium requires that transitions in 

each direction occur at equal rates. [75] 

The essential element missing from 10 needed to turn the 

triptycene directionally is some form of energy input to drive 

it away from equilibrium and break the detailed balance. In 

principle,this could be achieved rather simply for 10 by a 

periodic fluctuation in temperature (causing directional 

Figure 12. a) Kelly’s molecular realization (10) of Feynman’s adiabatic 

ratchet and pawl which does not rotate directionally at equilibrium. [72] 

b) Schematic representation of the calculated enthalpy changes for 

rotation around the single degree of internal rotational freedom in 10. 

1 H 


Chemie 

rotation in chemical structures does not have to be complicated),thus 

constituting a temperature ratchet. [75] However, 

proving this experimentally by quantifying the net rotation 

appears to be nontrivial. As a different solution,Kelly et al. 

proposed a modified version of the ratchet structure (11a, 

Scheme 3),in which a chemical reaction is used as the source 

of energy. [76] If the amino group is ignored,all three energy 

Scheme 3. A chemically powered unidirectional rotor. [76] Priming of the rotor in its initial state with 

phosgene (11a!12 a) allows a chemical reaction to take place when the helicene rotates far enough up 

its potential well towards the blocking triptycene arm (12b). This gives a tethered state 13 a, for which 

rotation over the barrier to 13 b is an exergonic process that occurs under thermal activation. Finally, the 

urethane linker can be cleaved to give the original molecule with the components rotated by 1208 with 

respect to each other (11b). 

minima for the position of the helicene with respect to the 

triptycene “teeth” are identical: the energy profile for 3608 

rotation would appear as three equal energy minima, 

separated by equal barriers. As the helicene oscillates back 

and forth in a trough,however,sometimes it will come close 

enough to the amine for a chemical reaction to occur (as in 

12b). Priming the system with a chemical “fuel” (phosgene in 

this case to give the isocyanate 12a) results in “ratcheting” of 

the motion some way up the energy barrier (13a). Continuation 

of the rotation in the same direction,over the energy 

barrier,can occur under thermal control and is now an 

exergonic process (giving 13b) before cleavage of the 

urethane gives the system rotated by 1208 (11 b). Although 

the current version of the system can only carry out one third 

of a full rotation,it demonstrates the principles required for a 

fully operating and cyclable rotary system under chemical 

control and represents a major advance in the experimental 

realization of molecular-level machines. 

Exemplified by the motor proteins from nature,continually 

operating (autonomous) chemically powered molecular 

motors may be classified as a subset of catalysts—catalyzing 

the conversion of high-energy “fuel” molecules into lower 

energy products while undergoing a conformational change 

but returning to the starting state on completion of each cycle. 


87

Reviews 

Mock and Ochwat have proposed 14,which undergoes the 

catalytic cycle illustrated in Scheme 4,as a minimalist model 

of a molecular motor. [77] In the process of catalyzing the 

hydration of its ketenimine fuel (red box) to give a 

Scheme 4. Proposed system for chemically driven directional 1808 

rotary motion fueled by hydration of a ketenimine (red box). [77] For 

clarity, the catalytic cycle for a single enantiomer of motor 14 is shown. 

This cycle produces the opposite enantiomer, which undergoes an 

analogous cycle in which rotation must be biased in the opposite 

direction. A number of potential side reactions (not illustrated) which 

would divert the system from the catalytic cycle were found to be 

kinetically insignificant under the reaction conditions employed. 

carboxamide waste product (blue box),epimerization of the 

stereogenic center in the motor occurs—formally rotation 

around a C O bond (as indicated for (R)-14 in Scheme 4). 

The cycle operates (Scheme 4) under the specific kinetic 

conditions k 2,k 4 > k 1[AcCH=C=NtBu] > k 3[H 2O]. Kinetic 

analysis based on spectrophotometric measurements was 

used to identify reaction conditions under which this relation 

is satisfied. Over a single catalytic cycle,therefore,the 

molecular chirality should ensure some biasing of the rotational 

direction for formal 1808 rotation around the C O 

bond. However,the subsequent cycle on the opposite 

enantiomer will experience the antipodal directing effect so 

that the biasing effect is the exact reverse to before. [78] 

The restriction of rotational motion arising from steric 

interactions between ortho substituents in biphenyl systems 

forms the basis for another system designed to exhibit 

directional rotation through ring opening/ring closing of a 

chiral lactone (Scheme 5). [79] Ring opening of lactone 15 with 

a bulky nucleophile should proceed preferentially through 

attack at one of the two diastereotopic faces (k 15!16-aS > 

k 15!16-aR). Equilibration of the ring-opened diastereomers 

should then occur by random oscillations around the aryl–aryl 

bond,with the bulky nucleophile preferentially avoiding 

passing over the cyclohexanol ring. Ring closing is then 

proposed to be faster from the 16-aR isomer because of the 

proximity of the reacting groups,so that a net 3608 rotation 

will be accomplished by a number of molecules in the system. 

Experimentally,equilibration of the two ring-opened diastereomers 

in the current system occurs too fast for determination 

of the selectivity of the ring-opening reaction. Similarly,demonstrating 

directional selectivity for the ringclosing 

step will present a significant challenge. A further 


Scheme 5. Proposed system for unidirectional rotation around an aryl– 

aryl bond based on ring opening/ring closing of a chiral lactone. [79] 

Although this cannot function at equilibrium, it could if additional 

features were added such that k 15!16-aS ¼6 k 16-aS!15 and k 15!16-aR ¼6 

k 16-aR!15. 

modification is also necessary to achieve directional 3608 

rotation; since the ring-closing step is the exact reverse of the 

ring-opening step,both must proceed by the same transition 

state so that the rate in either direction is the same (k 15!16-aS = 

k 16-aS!15 and k 15!16-aR = k 16-aR!15). No energy would be consumed 

by the mechanism proposed in Scheme 5 and,of 

course,the principle of detailed balance (Section 1.4.1) 

demands that unidirectional rotation cannot occur in a 

system at equilibrium. 

Stereoselective ring opening of racemic biaryl lactones 

using chiral reagents results in a directional rotation of about 

908,which can be extended to a full half-turn by chemoselective 

ring closing to give the lactone by using a hydroxy 

group in the other ortho position. This effect has been 

demonstrated by Branchaud and co-workers [80] and,in an 

independent effort,Feringa and co-workers have successfully 

extended this strategy to obtain a full 3608 rotation around a 

C C single bond. [81] The process involves four intermediates 

(A–D,Figure 13 a),in each of which rotation around the 

biaryl bond is restricted: by covalent attachment in A and C, 

and through nonbonded interactions in B and D. Directional 

rotation to interchange these intermediates requires a stereoselective 

bond-breaking reaction in steps (1) and (3) and a 

regioselective bond-formation reaction in steps (2) and (4). 

Unlike 15 above,lactones 17 and 19 (Figure 13 b) exist as 

racemic mixtures as a result of a low barrier for small 

amplitude rotations around the aryl–aryl bond. Reductive 

ring opening with high enantioselectivity is,however,achievable 

for either lactone by using a homochiral borolidine 

catalyst,and the released phenol can subsequently be 

orthogonally protected to give 18a or 20 a. The ring-opened 

compounds are produced in near-enantiopure form in a 

process which involves directional rotation of 908 around the 

biaryl bond,governed by the chirality of the catalyst,and 

powered by consumption of borane. The ortho substitution of 

these species results in a high barrier to axial rotation. 

Oxidation of the benzylic alcohol (18 a!18 b or 20 a!20b) 

primes the motor for the next rotational step. Selective 



Figure 13. a) Schematic representation of unidirectional rotation around a single bond, through four states. [81] In states A and C rotation is 

restricted by a covalent linkage, but the allowed motion results in helix inversion. In states B and D rotation is restricted by nonbonded 

interactions between the two halves of the system (red and green/blue). These forms are configurationally stable. The rotation relies on 

stereospecific cleavage of the covalent linkages in steps (1) and (3), then regiospecific formation of covalent linkages in steps (2) and (4). 

b) Structure and chemical transformations of a unidirectional rotor. Reactions: 1) Stereoselective reduction with (S)-CBS then allyl protection. 

2) Chemoselective removal of the PMB group resulting in spontaneous lactonization. 3) Stereoselective reduction with (S)-CBS then protection 

with a PMB group. 4) Chemoselective removal of the allyl group resulting in spontaneous lactonization. 5)Oxidation to carboxylic acid. 

removal of one of the protecting groups on the enantiotopic 

phenols results in spontaneous lactonization when thermally 

driven axial rotation brings the two reactive groups 

together—again probably a net directional process because 

of the steric hindrance of the ortho substituents (although this 

is not demonstrated because the chirality is destroyed in this 

step). Figure 13b illustrates the unidirectional process achieved 

using the (S)-Corey–Bakshi–Shibata ((S)-CBS) catalyst; 

rotation in the opposite sense can be achieved by 

employing the opposite borolidine enantiomer and swapping 

the order of phenol protection and deprotection steps. 

2.1.3. Stimuli-Induced Conformational Control in 

Organometallic Systems 

Controlling the facile rotary motion of 

ligands in metal sandwich or double-decker 

complexes (introduced in Section 2.1.1) is conceptually 

similar to controlling rotation around 

covalent single bonds,and stimuli-induced 

control in such metal complexes has also been 

demonstrated. In metal bisporphyrinate complexes 

such as [Ce(21)] (Scheme 6) rotary 

motion corresponds to enantiomerization 

when the ligands possess D 2h symmetry. This 

situation provides a convenient handle for 

monitoring the kinetics of rotation. [82] In complex 

[Ce(21)],rotation around the metal center 

is slow enough to permit isolation of the two 

enantiomers by chiral HPLC. However,reduc- 


Chemie 

tion of the metal center ([Ce IV (21)]![Ce III (21)] ) increases 

the rate of racemization by over 300-fold. [82c] This effect is 

thought to derive from a reduced p–p interaction between the 

two ligands as a consequence of the larger ionic radius of the 

metal center in the lower oxidation state. Similarly,complexes 

formed around the smaller Zr IV ion show very slow rotational 

dynamics at pH 7, [83] yet protonation results in facile racemization. 

[82a] The effect is retarded by oxidation of the 

porphyrin ligands,probably as a result of electrostatic 

repulsion of incoming protons,but also because of the fact 

that the highest occupied molecular orbital (HOMO) of the 

complex is antibonding,so removal of electrons should 

Scheme 6. Controlling the rate of relative rotations of porphyrin ligands in cerium bis[tetrakisarylporphyrinate] 

double-decker complex [Ce(21)]. [82c] 


89

Reviews 

increase the p–p bonding interaction between the two 

porphyrin rings. [82c] 

Rotary motion in sandwich complexes can be interrupted 

by the binding of a ditopic guest between recognition sites on 

each of the two rings. If more than one such pair of binding 

sites exists,a positive,homotropic allosteric effect is 

observed. [84] This principle has been exploited to create 

allosteric receptors (for example, 22) for g-dicarboxylic 

acids (Scheme 7), [85] b-dicarboxylate anions, [86] potassium 

Scheme 7. Positive homotropic allosteric binding in a double-decker complex 22. [85] 

A result of the cooperative binding is pronounced guest selectivity; for example, ddicarboxylic 

acids are not bound. The chirality of the guest is communicated to the host, 

thus determining the sense of the axial chirality induced about the metal–porphyrin axis. 

ions, [87] silver ions, [88] as well as mono- and oligosaccharides 

(even in aqueous solution). [89] It was originally proposed that 

such effects were primarily a result of the restriction of the 

motion of the porphyrin ring when the first guest binds,thus 

reducing the entropic cost of subsequent identical binding 

events. [85–87,89] In the case of cooperative binding of silver ions, 

however,it is observed that binding of the guest species 

progressively and nonlinearly increases the rate of rotation. 

[88b] Here,cation binding induces a deformation of the 

porphyrin rings away from planarity to generate a more 

domed structure,simultaneously weakening the p–p interactions 

between the porphyrin rings and preorganizing the 

remaining silver binding sites. Recent results suggest that 

torsional strain induced by binding may play a significant role 

in the cooperative binding in all these systems. [90,91] 

Ferrocene has long been known to exhibit a low barrier to 

cyclopentadienyl (Cp) ring rotation. [92] Recently,a gas-phase 

experimental and theoretical study of dianionic 23 2 

and 

anionic [23·H] indicated that a two-state rotary switch could 

be operated by monoprotonation and deprotonation 

(Scheme 8). [93] The conformation of the dianion is governed 

by coulombic repulsions,while an intramolecular hydrogen 

bond stabilizes the observed conformation in the monoanion. 


Scheme 8. Proton-switched intramolecular rotation in a ferrocene 

derivative. [93] The amplitude of relative rotary motion of the two 

cyclopentadienyl ligands is about 1128. 

In contrast to these simpler metallocene or bis- 

(porphyrinate) examples,metallacarboranes tend to 

have rather high barriers to rotation around the metal– 

ligand axis. Dicarbollide ligand 24 2 

features two 

adjacent carbon atoms on its bonding face which 

imparts a dipole moment perpendicular to the metal– 

ligand axis (Figure 14a). Transoid complexes are 

normally preferred to minimize electrostatic repulsion. 

[94] Two exceptions,however,are the Ni IV or Pd IV 

complexes which are cisoid. [95] Complex [Ni(24) 2] can 

therefore operate as a reversible rotary switch on 

manipulation of the oxidation state or by photoexcitation 

(Figure 14b). [96] 

2.1.4. Stimuli-Induced Conformational Control around 

Several Covalent Bonds 

With an external stimulus,it is possible to control 

the conformation around not just one bond,but 

several all at once. Conformational control in biopolymers 

is of great importance in structural biology,and 

a vast array of methods for artificially triggering, 

altering,and reversing folding in polypeptides and 

polysaccharides now exists. [97] In nature,as in artificial 

systems,host–guest binding is often used to trigger 

complex conformational changes in one or both of the 

interacting species. In some cases this involves no more than 

minor bond deformations or the restriction of a few rotational 

degrees of freedom. In others,molecular recognition results 

in significant changes to a single degree of freedom (see 

Section 2.1.3),yet binding of one chemical species to another 

can also often result in significant changes to the conforma- 

Figure 14. a) Dicarbollide ligand 24 2 . b) Metallacarborane [Ni(24) 2]as 

an electrochemically controlled rotary switch. [96] The cisoid–transoid 

exchange involves a rotation of 1448. Both formal reduction and 

photochemical excitation of [Ni IV (24) 2] populate the lowest unoccupied 

molecular orbital (LUMO) and therefore elicit similar dynamic 

responses. Black spheres represent boron atoms, white spheres 

carbon atoms. 



tion and internal motion around several bonds. Such 

“induced fit” mechanisms are the basis of many 

allosteric systems,whereby recognition of one species 

affects the binding properties or enzymatic activity at a 

remote site in the same molecule. Allosterism,cooperativity,and 

feedback are central to many functional 

biological systems [98] and synthetic approaches towards 

achieving similar effects have been extensively reviewed 

elsewhere. [84,99] Here we are interested primarily in the 

dynamic processes themselves and,therefore,in many 

cases where the conformational changes are rather small 

or poorly defined,such systems do not fall under our 

definition of molecular machines. However,certain 

examples do exhibit impressive control over the molecular 

shape or conformation and merit discussion here in 

their own right,together with other examples of stimuliinduced 

conformational changes around several bonds. 

Some of the first and most elegant examples of 

synthetic allosteric receptors were introduced by Rebek 

et al. (Scheme 9). [99a,100] In 25,the binding of a metal ion 

such as tungsten to the bipyridyl ligand forces coplanarity 

of this unit,thus distorting the crown ether 

conformation and diminishing its ability to bind potas- 

Scheme 9. a) Negative heterotropic allosteric receptor 25 binds alkali metal ions, with selectivity 

for K + . [100] Chelation of tungsten to the bipyridyl moiety forces this unit to adopt a rigid 

conformation in which the 3 and 3’ substituents are brought close together. The resulting 

conformation of the crown ether does not favor binding through all the oxygen atoms and so 

affinity for K + ions is reduced. In fact [W(CO) 3(25)] shows a preference for binding the smaller 

Na + ion. b) Positive homotropic allosteric receptor 26. [101] 

sium ions—a negative heterotropic allosteric effect. The same 

research group later developed this concept to create positive, 

homotropic allosteric receptor 26,in which binding one 

molecule of Hg(CN) 2 preorganizes the remaining binding site 

for a second binding event. [101] These strategies have since 

either directly spawned or indirectly inspired an extraordinarily 

wide range of increasingly sophisticated synthetic 

allosteric receptors. [84,99] 

Binding to molecular tweezer and clip receptors 

(Figure 15) can result in significant conformational changes 

in the host,as favorable interactions with the guest are 

maximized. In 27,for example,the distance between the 

sidewalls decreases from 14.5 to 6.5 Š on binding to aromatic 

guests, [102] while diphenylglycouril-based clips such as 28 do 


Chemie 

Figure 15. Binding-induced conformational changes in molecular clips. a) Dimethylenebridged 

aromatic clip 27 in which binding to 1,2,4,5-tetracyanobenzene results in a 

large-amplitude induced-fit conformational change (motion indicated by arrows). [102] 

b) The three accessible conformations of the diphenylglycouril-based clips illustrated 

for simple derivative 28 (methoxy substituents are not shown on the space-filling 

models). [103] The syn,anti (sa) form dominates in solution, but only the anti,anti form is 

able to bind aromatic guests—in an induced-fit mechanism. c) Glycouril-based clip 29 

in which an additional binding site (a crown ether) can control the conformation of the 

clip molecule, preorganizing the p-electron-rich binding site and resulting in a positive, 

heterotropic allosteric effect. [104] The space-filling representations are reprinted with 

permission from Ref. [103a]. 

not principally adopt the anti,anti (aa) 

binding conformation,only doing so in 

the presence of a suitable guest. [103] 

Similar structures can incorporate two 

conformationally coupled binding sites 

and exhibit allosteric effects. Glycourilbased 

clip 29 bears two crown ether 

substituents and binds potassium ions 

to form a complex with 1:2 stoichiometry. 

The binding event stabilizes the 

aa conformation,preorganizing the 

electron-rich naphthalene units in a 

pseudoparallel arrangement,thus 

increasing the binding affinity for 

simple electron-poor aromatic compounds 

such as 1,3-dinitrobenzene. [104] 

In atropoisomeric host molecules,an 

induced-fit binding process at elevated 

temperatures can be used to dynamically 

select the single optimal binding 

conformation for a particular guest, 

which can then be “saved” by cooling the system to ambient 

temperature and removal of the templating guest. [105] 

The addition of an external ligand or guest can also be 

used to disrupt a preexisting intramolecular interaction and 

cause a change in conformation. This is the case for 4,4’bipyridyl-capped 

zinc porphyrin 30 in which the pyridyl and 

porphyrin planes are switched from perpendicular to mutually 

parallel on addition of pyridine (Scheme10). [106] 

It is well known that the relative stabilities of the two 

different chair forms of six-membered alicyclic rings can be 

manipulated by covalent substitutions. [107,108] However,in 

trisaccharide 31 this conformational change can be achieved 

by adding and removing metal ions (Scheme 11). [109] In the 

absence of metal ions,the 4 C 1 conformation is preferred for 


91

Reviews 

Scheme 10. Conformational switching in capped porphyrin 30. [106] 

Scheme 11. Chelation-induced conformational control in a 

trisaccharide. [109b] 

the central “hinge” pyranose unit,in which all the substituents 

are equatorial and both ends of the molecule are far apart. On 

addition of Pt II ions,however,a ring flip to the 1 C 4 form is 

observed so that the amine units can chelate to the metal ion 

and results in a major change in the shape of the oligosaccharide. 

Removal of the metal ions with NaCN returns the 

trisaccharide to its original extended conformation. Such 

stimuli-induced conformational switching has been achieved 

in a variety of cyclic systems through binding of metal ions [110] 

and variation of the pH value. [111] In addition to having 

significance for the control and modeling of biologically 

relevant oligosaccharides, [112] such systems have served as 

inspiration for the development of synthetic conformational 

switches (see Section 8.2.1). 

Well-defined large amplitude (sometimes very large 

amplitude; see Section 8.2.1) conformational changes can be 

induced in cavitands derived from resorcin[4]arenes (for 

example, 32,Scheme 12). [113] These molecules can exist in 

either an open “kite” conformation or a narrower “vase” 

form. As a result of solvation effects,the kite form is generally 

favored at low temperatures and the vase form at high 

temperatures. [114] Recently,it has been demonstrated that 

reversible switching between the two can also be achieved at 

room temperature through protonation of the quinoxaline 

nitrogen atoms, [115] or coordination of metal ions to these 

same atoms, [116] while the switching can also be highly 

dependent on the solvent. [115b,c] In a related series of cavitands 

bearing amide substituents around the rim,the kite form is 

stabilized by dimerization (so-called “velcrands” forming 

“velcraplexes”),which is driven by intermolecular hydrogen- 


Scheme 12. Conformational bistability in resorcin[4]arene cavitands 32. 

Reversible switching between the two forms can be achieved with a 

number of stimuli: a) by changing the temperature; for example, for 

R = Me in CDCl 3/CS 2:1)T < 211 K; 2) T > 318 K; [114] b) by changing the 

pH value; for example, for R = 3,5-di(tert-butyl)phenylmethyl in CDCl 3 

at T = 298 K: 1) CF 3COOH; 2) K 2CO 3; [115] c) by adding metal ions; for 

example, for R = n-Hex in CDCl 3 at 295 K: 1) ZnI 2 in [D 4]methanol; 

2) excess [D 4]methanol. [116] 

bonding,van der Waals,and solvophobic forces. Increasing 

the temperature or solvent polarity,as well as the introduction 

of suitable guest species,can induce switching to the monomeric 

vase forms. [117] Conversely,the use of amide substituents 

that are able to stabilize the vase form through intramolecular 

hydrogen bonding results in kinetically stable 

inclusion complexes in the presence of a suitable guest. [118] 

Incorporation of metal-ligating carboxymethylphosphonate 

groups into these structures allows switching of the preferred 

conformation from vase to kite,along with concomitant 

release of any encapsulated guest,on addition of lanthanum 

ions. [119] The reverse process occurs on addition of a competing 

ligand for the metal ion. The calixarene family,in general, 

clearly share this potential for interesting conformational 

dynamics, [120] and in certain cases significant degrees of 

control over these can be achieved,thus resulting in a 

number of induced-fit and allosteric receptor systems. [121] 

Rather than adding an external species to induce a 

conformational change on binding,intramolecular interactions 

between two parts of the same molecule can be 

controlled remotely to bring about changes in the geometry. 

Macrocyclic compound 33 4+ preferentially adopts the selfcomplexed 

conformation shown in Scheme 13,which is 

stabilized both by p–p charge-transfer interactions and by 

hydrogen bonds. [122] Electrochemical reduction of the cyclophane,however,“switches 

off” these interactions and the 

molecule adopts a (poorly defined) conformation in which the 

dioxynaphthalene unit is no longer encapsulated by the 

macrocycle. [123] 

The formation of excimers or exciplexes between two 

chromophores in the same molecule is another way by which 

intramolecular interactions may be remotely controlled so as 

to effect a conformational change. Most examples,however, 

involve flexible,linear ground states with poorly defined 

geometries. [124] In certain donor–bridge–acceptor systems,a 

conformational change does not occur in the initial photochemically 

excited state,rather,electron transfer occurs to 

give an “extended charge transfer” species. Depending on the 



Scheme 13. Electrochemically induced conformational motion based on remote control of intramolecular 

interactions. [122] 

rigidity of the structure,electrostatic attraction 

can then drive a conformational change to a 

“compact charge transfer” state. Such systems 

are often referred to as “molecular harpoons”. 

[125] 

In recent years,a number of oligomeric 

synthetic systems have been investigated in 

solution for their ability to adopt well-defined 

conformations with interesting and tunable 

secondary and tertiary structures,particularly 

those of a helical nature. [126] Oligomeric phenylacetylenes,for 

example,form helical structures 

in polar solvents as a result of solvophobic 

interactions and thus exhibit solvent- and 

temperature-sensitive secondary structures. 

[127,128] Aromatic oligoamide foldamers, 

on the other hand,adopt helical conformations 

in nonpolar solutions,and in the solid state, 

given suitably arranged hydrogen-bonding 

substituents. [126h-j] For heptamer 34,helix formation 

is driven by intramolecular hydrogen 

bonding between the amide groups and pyridine 

units (Figure 16 a). [129] Under certain conditions,double 

helices (in which two strands of 

the same oligomeric monomer are intertwined) 

are formed. This structure is mainly 

stabilized through intermolecular p–p stacking 

interactions,with hydrogen bonding determining 

the helical conformation of each strand. 

The double-helix structure is asymmetric,with 

each end of a strand in different environments. Interconversion 

of two equivalent forms occurs by a rotational corkscrew 

motion of one strand relative to the other. Significant heating 

is required to cause the much larger conformational changes 

required to bring the system into the single-helix regime 

(Figure 16 b). [129a,c] 

In closely related heptamer, 35,the single-helix secondary 

structure is disrupted upon protonation of the four diaminopyridine 

units,thus giving an extended linear conformation 

(35·(H + ) 4,Scheme 14). [130] Further protonation of the three 

remaining dicarboxypyridine moieties yields a second helical 

arrangement (35·(H + ) 7),which on deprotonation can be 

returned through the linear tetraprotonated form back to 

the neutral helix. A pentadecamer analogue has recently been 

shown to undergo a similar reversible uncoiling/coiling transformation,which 

results in a remarkable change in the overall 


Chemie 

length from 12.5 to 57 Š. [131] Using 

the same principles of altering 

hydrogen-bonding arrangements, 

conformational switching can be 

achieved in a different aromatic 

oligoamide system in which the 

protonation state of a repeating 

phenol functionality is controlled. 

[132] 

Oligoheterocyclic strands consisting 

of alternating a,a’-connected 

pyridine and pyrimidine 

Figure 16. a) Chemical structure and folding of heptameric aromatic polyamide 34 (see 

Scheme 14 for representation of the hydrogen-bonding arrangement responsible for the folding). 

[129] b) In concentrated solutions, 34 dimerizes to form double helices. The double-helix 

structure is dissymmetrical and interconversion between the two equivalent forms occurs through 

a relative corkscrew motion of the two monomers. Exchange with the monomeric species is slow, 

as dissociation of the dimer involves unwinding of the helix structure. The ribbon representations 

are reprinted with permission from Ref. [129a]. 

subunits adopt coiled structures because of the preferred 

transoid conformation at each heterocycle linkage. [133] However,the 

binding of a metal cation stabilizes the cisoid 

arrangement of the terpyridine-like coordination sites. In the 

presence of Pb II ions,for example,helix 36 is converted into 

an extended linear arrangement (a “[5]-rack” complex, 

Scheme 15). Again this process results in an enormous 

change in the molecular length,from 7.5 to 38 Š,and can 

be carried out reversibly and repeatedly by employing 

cryptand 37 to sequester and release Pb II ions depending on 

the pH value of the environment. [134] By contrast, a,a’-linked 

pyridine units naturally form linear arrangements. Although 

oligomers of this type are challenging to prepare,hydrazones 

can be used as isosteric replacements for alternate pyridine 

units,thus allowing preparation of linear pyridine–hydrazone 

sequences. These systems undergo the reverse process to that 


93

Reviews 

Scheme 14. pH-controlled helix formation for aromatic polyamide 

heptamer 35. The insets show the hydrogen-bonding arrangements 

responsible for the helical structures. [130] 

illustrated for 36,namely,they form linear chains in solution 

which can be reversibly coiled around divalent metal ions. [135] 

Oligoheterocyclic systems such as 36 can also form 

double-helix structures. Whereas single/double helix interconversion 

for the aromatic oligoamide systems in Figure 16 


is controlled by the solvent,concentration,and temperature, 

pyrimidine–pyridine oligomers can be made to form double 

helices by complexation to metal ions. Addition of Ag I ions to 

helical compound 38,for example,results in the formation of 

double-helical dimers of formula [(Ag I ) 2(38) 2] 2+ ,with the two 

metal ions bound at opposite ends of the chain and extensive 

intermolecular p–p stacking between the intertwined strands 

(Figure 17). [136] The single/double helix interconversion process 

can be achieved reversibly in a manner analogous to that 

in Scheme 15. 

Figure 17. pH-switched contraction and extension by metal ion triggered 

single/double helix interconversion. [136] On models of 38 and 

[(Ag I ) 2(38) 2] 2+ , SPr substituents have been omitted for clarity. The 

model structures are reprinted with permission from Ref. [136]. 

Scheme 15. pH-switched helix formation using a metal-ion template. [134] Counterions (CF 3SO 3 ) and solvent (CH 3CN), which complete the Pb II 

coordination sphere in the [5]-rack complex [(Pb II ) 5(36)] 10+ , are omitted for clarity, as have the SPr substituents in the space-filling models. The 

space-filling representations are reprinted with permission from Ref. [134]. 



A similar mechanism applies to 39,in which the two 

anthracene groups are held in a parallel arrangement,thereby 

creating a molecular tweezerlike cavity in which electronpoor 

guests such as 2,4,7-trinitro-9-fluorenone (TNF) can be 

bound (Scheme 16a). [137] Addition of cuprous ions,however, 

results in a cisoid–cisoid arrangement of the triheterocyclic 

unit so as to provide bipyridyl-like ligand environments for 

the metal ions. This separates the tweezer arms and releases 

the bound guest. Conversely,in 40,the oligoheterocyclic 

portion is designed so that the electron-rich binding cavity is 

only set up on ion binding (Zn II 

is used in this case, 

Scheme 16b). 

Salen/salophen ligand 41 is not intrinsically helical,but it 

forms helical structures on coordination to tetradentate metal 

ions such as Cu II or Ni II . [138] Electrochemical reduction of the 

Cu II -templated helix in a coordinating environment causes a 

reversible disruption of the helical secondary structure as the 

Cu I center prefers to adopt a pentacoordinate geometry in the 

absence of any tetrahedral ligand (Scheme 17). 

Finally,significant stimuli-induced conformational 

changes have also been achieved in a number of truly 

polymeric systems. More often than not,these are accompanied 

by detectable macroscopic changes in the material and 

will be discussed further in Section 8.3.3. 

Scheme 16. Cation-induced substrate release and binding as a result of large-amplitude conformational changes. [137] a) On binding cuprous ions, 

U-shaped tweezerlike receptor 39 is forced to adopt a cisoid conformation at the pyridyl–pyrimidine linkages, thus separating the electron-rich 

tweezer “arms” and releasing the electron-poor guest. Dicuprous W-shaped derivative [(Cu I ) 2(39)] 2+ is only formed on addition of large excesses 

of [Cu(MeCN) 4] + (> 8 equiv). b) On binding zinc ions, W-shaped terpyridine 40 adopts a U shape, thus aligning the electron-rich anthracene 

moieties so that electron-poor guests can be intercalated in the cavity. 

Scheme 17. Formation of a helical complex ([Cu II (41)]) from a nonhelical ligand and electrochemically induced reversible unfolding of the helix. [138] 


Chemie 


95

Reviews 

2.1.5. Torsional Control Arising from Molecular Orbital Symmetry 

The stereochemical outcome of many chemical reactions 

arises from the relative movements of groups,which are 

determined by orbital symmetry considerations,most 

famously those governed by the Woodward–Hoffmann 

rules. [139] A full discussion of this area is beyond the scope 

of the current Review,but it is worth noting that such 

mechanisms for controlling submolecular motions in molecular-machine 

systems have been particularly underexploited 

to date. However,a purely electronically driven correlated 

rotational process has been observed in carbonium ion 

tricobalt complexes,driven by maintaining favorable overlaps 

between a molecular orbital centered on the three metal 

centers and an orbital belonging to the organic fragment as it 

moves between three degenerate conformational positions. 

[140] Recently,an interesting molecular dynamics study 

on 5-methyltropolone (42,Scheme 18),showed that proton 

transfer at the a-hydroxyketone should directly result in 

rotation of the methyl group at the 5-position. [141] This is 

explained by a coupling of the p system to the methyl group 

through hyperconjugation (involving two of the three methyl 

hydrogen 1s orbitals). Overlap of the HOMO of the methyl 

group with the LUMO of the ring is therefore strongest when 

the two out-of-plane hydrogen atoms straddle a single bond in 

the ring. As proton transfer results in tautomerization and 

bond alternation round the 

ring,this flips the preferred 

orientation of the methyl 

group and a 608 rotation 

occurs. 

2.2. Controlling 

Configurational Changes 

Changes in configuration, 

[142] 

in particular cis– 

trans isomerization of double 

bonds,have been widely studied 

from theoretical,chemical,and 

biological perspectives. 

[107,143] Although the 

small amplitude motion 

involved is not generally sufficient 

for direct exploitation 

as a machine,it can provide 

an extremely useful photoswitchable 

control mechanism 

for more complex systems 

(see below) and,in some 

cases,can even be harnessed 

to perform a significant 

mechanical task. Such systems 

represent some of the 

first examples of molecularlevel 

motion which can be 

controlled by the application 

of an external stimulus. 


Scheme 18. Coupling of proton transfer to rotation of a methyl group 

in 5-methyltropolone (42). [141] 

As a prototypical example of this type of system,the 

photoisomerization of stilbenes has been extensively studied 

for well over 50 years. [144] As organic photochemistry developed,other 

important photochromic systems were discovered 

(Scheme 19): [145] the photoisomerization of azobenzenes, [146] 

the reversible electrocyclization of diarylethenes, [147] 

the 

photochromic reactions of fulgides, [148] the interconversion 

of spiropyrans with merocyanine (and the associated spirooxazine/merocyanine 

system), [149] as well as chiroptical switching 

in overcrowded alkenes (for example, 45,Scheme 21). [150] 

All these processes are accompanied by marked changes in 

both physical and chemical properties,such as color,charge, 

and stereochemistry,and a wide range of applications based 

on their switching properties have both been proposed and,in 

some cases,realized,from liquid crystal display technology to 

Scheme 19. Archetypical examples of photochromic systems that give a mechanical response. a), b) The 

cis–trans isomerization of stilbenes [144] and azobenzenes, [146] respectively. c) The reversible photochemical 

electrocyclization of a diarylethene. [147] This can be a competing process in the cis–trans isomerization of 

stilbenes (a) and is observed for a number of heterocyclic and non-heterocyclic aromatic compounds joined 

through a C=C bond. The methyl groups shown prevent irreversible loss of H 2 to give a tricyclic aromatic 

compound, while substitution of the double bond prevents cis!trans isomerization. d) The reversible 

photochemical electrocyclization of a fulgide. [148] Again, a number of substitution patterns are tolerated 

(cis–trans isomerization around either double bond may occur, but is undesirable). e) The photochemical 

interconversion of spiropyrans with their ring-open, zwitterionic merocyanine forms. [149] Analogues in which 

the benzylic carbon atom of the double bond is replaced with a nitrogen atom (spirooxazines) undergo a 

similar transition. 



variable-tint spectacles and optical recording media. [151] Most 

of these applications simply rely on the intrinsic electronic 

and spectroscopic changes on interconversion between the 

two species. There are some cases,however,in which small 

configurational changes can be harnessed in a more mechanical 

fashion and the resulting devices can be considered to be 

like molecular machines. 

Various configurational changes (in particular,photoisomerization 

of azobenzene) have been employed to alter 

peptide structures,thereby creating semisynthetic biomaterials 

whose activity can be controlled photonically. [97n–u] These 

systems,which amplify the small configurational change of 

the synthetic unit to cause a significant change in the peptide 

secondary structure,mimic to some extent the role of proline 

and peptidylprolyl cis–trans isomerases [152] 

in controlling 

protein activity in cells. Recently,it has been shown that the 

effective helix length can be controlled by photoisomerization 

in synthetic oligomers similar to those discussed in Section 

2.1.4 but composed of alternating 2,6-dicarboxamide and 

m-(phenylazo)azobenzene units. [153] Incorporation of azobenzene 

or stilbene chromophores into dendritic molecules can 

result in interesting photochemical effects,as well as allowing 

amplification of the configurational change into large amplitude 

changes in molecular conformation or other properties. 

[154] These strategies are somewhat similar to the use of 

azobenzene units as phototriggers in polymeric synthetic 

materials (see Section 8.3.3). 

In small-molecule systems,converting a configurational 

change around a double bond into significant mechanical 

motion requires considerable ingenuity. Combining the 

reversible photoisomerization of an azobenzene with the 

“molecular-bearing” attributes of metallocene complexes 

(see Section 2.1.3),Aida and co-workers have created a pair 

of “molecular scissors” 43 (Scheme 20a). [155] The optically 

triggered change in the double-bond configuration brings 

about an angular change of position about the ferrocene 

“pivot” (green) and results in an opening and closing of the 

phenyl “blades” (red). Reversible switching is possible over a 

number of cycles,with the bite angle between the blades 

Scheme 20. a) “Molecular scissors” 43, in which photoisomerization 

of an azobenzene is converted into a 498 rotary motion around a 

metallocene bearing. [155] b) “Molecular hinge” 44, in which concerted 

configurational change of the two azobenzene units results in a 

change of approximately 908 in the angle between the planar xanthene 

units. [157] 

altered from approximately 98 when closed to more than 588 

when open. 

The concerted action of two azobenzene configurational 

switches [156] has been used to alter the angle between two 

planar moieties in a so-called “molecular hinge” 44 (Scheme 

20b). [157] In trans,trans-44,the two xanthene units are virtually 

coplanar. Photoisomerization to the cis,cis isomer occurs 

upon irradiation at 366 nm,thus resulting in an angle of 

almost 908 between the two aromatic ring systems. The high 

energy of the strained trans,cis form renders cis,cis-44 

remarkably thermally stable,but reisomerization can be 

achieved by irradiation at 436 nm. 

While investigating the use of overcrowded alkenes as 

chiroptical molecular switches, [150] Feringa et al. created a 

molecular brake, 45,in which the speed of rotation around an 

arene–arene single bond can be varied by changing the alkene 

configuration (Scheme 21). [158] Counterintuitively from the 

Scheme 21. Counterintuitive variation of kinetic barrier to rotation 

around an aryl–aryl bond by isomerization of the double bond in an 

overcrowded alkene. [158] Values for the free energy of activation (DG ° ) 

for the rotary motion in each configuration are shown. 


Chemie 

two-dimensional representations in Scheme 21,the rate of 

rotation around the indicated bond is actually faster in cis-45 

than in trans-45 (demonstrated by 1 H NMR spectroscopy)— 

the naphthalene unit is flexible enough to bend away from the 

phenyl rotator unit,while the methylene protons on the other 

side of the double bond are rigidly held in equatorial and axial 

positions and present a significant steric barrier to the rotator. 

Unfortunately,the photochemical interconversion between 

the cis and trans forms is not efficient for this molecule, 

although the system stands as proof (see also rotaxanes 87–89, 

Scheme 51) that a change in configuration can alter not just 

the optical properties or bulk orientations,but can also 

control aspects of large amplitude submolecular motions. 

The chiral helicity in molecules such as 45 causes the 

photochemically induced trans–cis isomerization to occur 

unidirectionally according to the handedness of the helix. 

Accordingly,this system already possesses some of the 

features necessary for a unidirectional rotor and,indeed, 

the incorporation of one further chiral element [159] allowed 

the realization of the first synthetic molecular rotor capable of 

achieving a full and repetitive 3608 unidirectional rotation 

(Figure 18 a). [160,161] Irradiation (l > 280 nm) of this extraordinary 

molecule,(3R,3’R)-(P,P)-trans-46,causes chiral helicitydirected 

clockwise rotation of the upper half relative to the 

lower portion (as drawn),at the same time switching the 

configuration of the double bond and inverting the helicity to 

give (3R,3’R)-(M,M)-cis-46. However,this form is not stable 


97

Reviews 

Figure 18. Operational sequence (a) and potential energy profile (b) of 

the first light-driven unidirectional 3608 molecular rotary motor, 

(3R,3’R)-46. [160] Note, the labels “stable” and “unstable” in (a) refer to 

thermodynamic stability, and the reaction coordinate in (b) does not 

correspond directly to the angle of rotation around the central bond. 

Even at the steady state (> 280 nm and > 608C), net fluxes occur in 

each of the isomer interconversions that make up the reaction cycle. 

The energy profile is adapted with permission from Ref. [161b]. 

at temperatures above 55 8C as the methyl substituents on 

the cyclohexyl ring are placed in unfavorable equatorial 

positions. At ambient temperatures,therefore,the system 

relaxes through a second,thermally activated helix inversion 

to give (3R,3’R)-(P,P)-cis-46,with the substituents at either 

end of the double bond continuing to rotate in the same 

direction with respect to each other. Irradiation of (3R,3’R)- 

(P,P)-cis-46 (l > 280 nm) results in a second photoisomerization 

and helix inversion to give (3R,3’R)-(M, M)-trans-46. 

Again,the methyl substituents are placed in an energetically 

unfavorable position by the photoisomerization reaction and 

thermal relaxation (this time temperatures > 60 8C are 

required [162] ) completes the 3608 rotation of the olefin 

substituents,thereby regenerating the starting species 

(3R,3’R)-(P,P)-trans-46. As each different step in the cycle 

involves a change in helicity,the directionality of the process 

can be monitored through the change in the circular dichroism 

spectrum at each stage. The four states can be differently 

populated depending on the precise choice of wavelength and 

temperatures used,while irradiation at 280 nm at > 60 8C 


results in continuous 3608 rotation. [160] Figure 18 b shows the 

overall potential-energy changes during a full 3608 rotation. 

In terms of mechanism,the process essentially involves 

switching between two asymmetric potential energy surfaces 

(one each for the cis and trans diastereomers) which are 

spatially separated (in terms of their position along the 

reaction coordinate for rotation around the central bond). 

Furthermore,this switching process is directional (see above) 

and so this system bears many of the hallmarks of a 

dichotomous,stepwise traveling-wave ratchet (see Section 

1.4.2.1). The potential-energy minima and maxima on 

the cis and trans surfaces are of course actually slightly 

different,and so elements of a flashing ratchet are also 

present—such hybrids are perfectly acceptable under Brownian 

ratchet theory. [39f] 

Note that if 46 is irradiated at wavelengths greater than 

280 nm and at temperatures above 608C the system will reach 

a steady state at which point the bulk distribution of 

diastereomers no longer changes. Crucially,however,this 

steady state is not an adiabatic equilibrium. The steady state is 

maintained by a process (Figure 18) that features nonzero 

fluxes (corresponding to directional rotation of one component 

with respect to the other) between various pairs of 

diastereomers. In other words,as long as an external source of 

light and heat is supplied,the steady state in Figure 18 is 

effectively maintained by a cyclic process A!B!C!D!A 

(see Section 1.4.1),with the arrow indicating a net flux. Thus, 

even at the steady state, 46,and other molecules of this type, 

behave as directional rotary motors. 

As the photoisomerization process in such systems is 

extremely fast (< 300 ps), [163] the rate-limiting step in the 

operation of 46 is the slowest of the thermally activated 

isomerization reactions. The effect of molecular structure on 

this rate has been investigated in a series of derivatives. An 

ethyl substituent at the two stereogenic centers results in a 

moderate increase in the rates of thermal relaxation,probably 

because of greater steric hindrance when these groups occupy 

the unfavorable equatorial positions. [164] The isopropyl-substituted 

homologue showed a further increase in the rate for 

the thermal relaxation step between the cis diastereomers 

(fast even at 60 8C),but this trend was not followed for the 

equivalent step between the two trans diastereomers,which 

was very significantly retarded. This situation allowed the 

isolation of an intermediate meso-like isomer of the form 

(P,M)-trans,thus demonstrating that the thermal relaxation 

step in fact comprises two consecutive helix inversions, [164] inline 

with an earlier theoretical prediction. [162b] A second 

generation of motors (47–49,Scheme 22) was created in 

which “rotator” and “stator” sections of the molecule are 

differentiated (with a view to future applications; see 

Section 8.1) and in which only one stereogenic center is 

sufficient to direct the rotation. [165] For all the second 

generation motors shown in Scheme 22,the slowest thermal 

isomerization step has a lower kinetic barrier than in 46; in 

general,smaller bridging groups at Y and,in particular,at X 

result in the lowest activation barriers. Not all the kinetic 

effects of the structural changes turned out to be intuitive, 

however. Motor 48 contains an even smaller upper portion, 

yet the free energy of activation for the thermal isomerization 



Scheme 22. General structure of second-generation light-driven 

unidirectional rotors 47, 48, and the fastest member of this series, 

49. [165] Boc = tert-butyloxycarbonyl. 

process in this molecule is actually higher than its phenanthrene 

analogue (that is, 47;X= CH 2,Y= CH=CH,R 1 = R 2 = 

H). [165c] The decreased steric hindrance in 48 lowers the 

ground-state energy of the “unstable” isomer more than it 

lowers the transition-state energy for the thermal isomerization 

process. Conversely,a derivative bearing donor and 

acceptor substituents (47;X= S,Y = S,R 1 = NMe 2,R 2 = NO 2) 

exhibited thermal relaxation rates more comparable with less 

sterically encumbered examples. [165d] Furthermore,this molecule 

can operate using visible light,while protonation of the 

amine substituent led to slightly improved ratios for the 

photostationary state,which were reached in shorter irradiation 

times,but were then followed by slower thermal 

relaxation steps. It appears,therefore,that electronic effects 

also play an important role in the mechanism of these systems. 

This was further emphasized by derivative 49,in which an 

amine in the upper half of the molecule is directly conjugated 

with a ketone in the lower half. The consequent increase in 

single-bond character of the central olefin results in greatly 

increased rates for the thermal isomerization steps. [165e] 

Fast rotation rates have also been achieved with cyclopentane 

analogue 50 which can be accessed in higher 

synthetic yields than the six-membered 

ring compounds (Scheme 23). [166] 

Despite the greater conformational 

flexibility of the five-membered ring,a 

significant difference in the energies 

between the pseudoequatorial and 

pseudoaxial positions of the appended 

Scheme 23. Thirdgenerationunidirectional 

rotor 50. [166] In 

this case “ax” refers 

to the pseudoaxial 

orientation for substituents 

on the 

cyclopentyl ring. 

methyl groups still exists,and unidirectional 

rotation occurs. Both 49 and 50 

suffer from lower photostationary state 

ratios, [167] while the thermal relaxation 

steps for 49 are accompanied by a small 

amount of thermal back-isomerization. 

[165e,166a] However,neither of these 

factors affects the integrity of the process,as 

in all cases the thermal relaxa- 

tion steps are entirely unidirectional,thus ensuring the 

motion is ratcheted. Only the overall photon efficiency for 

rotation (a combination of quantum yield for the isomerization 

and the photostationary state ratio) is reduced. 

Recently,Feringa and co-workers have returned to the 

theme of using isomerization around the central olefin to 

control the rate of rotation of an aryl group in motor molecule 

51 (Scheme 24). [168] Although 51 displays more complex 

photochemistry than the previous motor molecules,it still 

exhibits unidirectional rotation around the olefinic bond. The 

Scheme 24. Rotational scheme for molecular motor 51 in which each 

diastereoisomer has a different barrier to rotation around the aryl–aryl 

bond indicated. [168] The terms “stable” and “unstable” refer to the 

thermodynamic stabilities of each isomer. 

rate of rotation around the aryl–aryl single bond was 

determined experimentally for each diastereoisomer and 

found to follow the order cis stable > cis unstable > trans stable > 

trans unstable. Similar to switch 45 (Scheme 21),therefore,the 

sp 3 -hybridized side of the dihydronaphthothiopyran part 

exerts the greater steric hindrance on the aryl rotator, 

particularly when the methyl substituent is in the less-favored 

equatorial position. Of course,the unidirectionality of the 

conversions between the four isomers is immaterial to the 

switching of the rotation rates. 

3. Controlling Motion in Supramolecular Systems 


Chemie 

Using an external stimulus to modulate the binding 

affinity of a host for a guest is the simplest expression of 

controllable molecular recognition. [169] A wide variety of 

stimuli can be employed to bring about changes,not just in 

geometric configuration,but also in electronic arrangement 

and environmental influences to modulate noncovalent 

interactions. Switchable host–guest systems teach us much 

about the nature of noncovalent interactions and how to 

manipulate them,although the requirement for kinetic 

association of components in a molecular machine rules out 

simple host–guest complexation where binding does not bring 

about a change in the conformation of either species or where 

transport of the guest between sites within the host is slow 

with respect to exchange with the bulk. For example,myosin 

must move along a track to which it is kinetically associated 

through a series of sequential binding events to bring about 


99

Reviews 

muscle contraction; no mechanical task occurs through simple 

“on”/“off” binding to the track by myosin molecules from the 

bulk. [170] In other words,simple host–guest/supramolecular 

systems cannot function as nanoscale mechanical machines 

unless restrictions on the motion of the unbound species apply 

or the binding event causes a mechanical (that is,conformational) 

change in one of the molecular components. A stimuliinduced 

molecular recognition event is neither a sufficient nor 

necessary condition for the construction of a molecular-level 

machine. 

3.1. Switchable Host–Guest Systems 

Whilst the requirement for kinetic association during the 

operation of the machine means that many switchable host– 

guest systems do not have the potential to act as mechanical 

machines,many still do. We have already seen that certain 

synthetic allosteric systems transmit binding at one site to a 

remote receptor through binding-induced conformational 

motions (see Sections 2.1.3 and 2.1.4). In other conformation-switching 

molecular machines,intermolecular binding 

events are both the stimulus and outcome of the molecularlevel 

motion. An early example of a switchable host–guest 

system which demonstrates molecular-machine-like characteristics 

is (E)/(Z)-52 (Scheme 25 a) developed by Shinkai 

et al. [171] These photoresponsive “molecular tweezers” exhibit 

high selectivity for binding large cations such as Rb + when in 

the cis form and selectivity for small cations such as Na + in the 

trans form. Furthermore,the presence of Rb + ions in solution 

increases the proportion of (Z)-52 at the photostationary state 

and decreases the rate of the thermal Z!E transformation. 

Subsequently,the same research group developed the “tailbiting” 

crown ether switchable receptor (E)/(Z)-53·H + 

(Scheme 25b). [172] In the (Z)-53·H + form,intramolecular 

binding of the ammonium ion to the crown ether prevents 

recognition of other cations in the medium,while thermal 

isomerization to give (E)-53·H + restores the properties of the 

crown ether necessary for binding alkali metal cations. It is 

also observed that the rate of Z!E isomerization is lowered 

(by 1.6–2.2 fold) for (Z)-53·H + relative to the deprotonated 

control compound (Z)-53. Crucially,the rate of this reaction 

increases as the concentration of K + ions in solution increases. 

Both these systems can therefore be viewed as primitive 

molecular machines in which a binding 

event at the crown ether unit(s) 

affects the isomerization processes of 

the azobenzene moiety with which it is 

kinetically associated. 

3.2. Intramachine Ion Translocation 

Metal–ligand binding interactions 

are often relatively kinetically inert 

and careful structural design has produced 

systems in which intramolecular 

motions are significantly favored 

over intermolecular exchange. [173] 

Scheme 25. Two of the earliest molecular machines. a) Photoresponsive 

molecular tweezers (E)/(Z)-52. [171] b) “Tail-biting” crown ether 

(E)/(Z)-53. [172] 

System 54 4+ (Scheme 26) consists of a coordinatively unsaturated 

Cu II center covalently linked to a redox-active Ni II – 

cyclam unit. [174] In this form,chloride anions bind strongly to 

the copper center,filling the vacant coordination site 

([54(Cl)] 3+ ). Electrochemical oxidation of the nickel center 

to Ni III dramatically increases its affinity for anions so that the 

chloride translocates to this new,more energetically favorable 

site. The motion is completely reversible on reduction of the 

nickel ion. In principle,the switching of the anion position 

could be an intermolecular process involving either free 

anions in solution or more than one molecule of 54. However, 

the anion translocation was demonstrated experimentally not 

to be concentration-dependent,in contrast to an analogous 

three-component system (Cu receptor + Ni receptor + Cl ) 

which exhibited strongly concentration-dependent behavior. 

Thermodynamic comparisons of the two systems suggest that 

the dominant mechanism in 54 is an intramolecular translocation,brought 

about by folding of the ditopic receptor. [175] 

Scheme 26. Redox-driven intramolecular anion translocation. [174] 




Calix[4]arene 55 reversibly translocates metal cations 

through protonation of the tertiary nitrogen atom 

(Scheme 27). [176] Dynamic 1 H NMR experiments indicate a 

high kinetic barrier to dissociation of the metal ion from the 

Scheme 27. Translocation of a silver cation between two sites in a 

calix[4]arene cavity: a “molecular syringe”. [176] 

neutral receptor,thus suggesting that upon protonation, 

translocation occurs intramolecularly through the cavity 

defined by the aromatic rings in a manner reminiscent of 

the action of a syringe. However,the protonated form exhibits 

much faster cation exchange with the bulk so the integrity of 

the stimuli-induced return stroke is probably less well 

maintained. [176] 

The first redox-driven cation-translocation system was 

reported by Shanzer and co-workers in helical complex 

[Fe III ·56],which exhibits strong evidence for a fully intramolecular 

process (Scheme 28). [177] The system exploits the 

preference of Fe III and Fe II ions for hard and soft ligands, 

respectively. Reduction of [Fe III (56)] with ascorbic acid 

Scheme 28. Redox-switched intramolecular cation translocation in a 

triple-stranded helical complex. [177] Reductant: ascorbic acid; oxidant: 

(NH 4) 2S 2O 8. 

generates [Fe II (56)(H) 3] 2+ which has spectral properties 

characteristic of the [Fe II (bipyridyl) 3] coordination sphere. 

Subsequent reoxidation ((NH4) 2S2O8) returns the system to 

its original state. The equivalent intermolecular process 

between two monotopic ligands does not occur under the 

same conditions,while even the translocation of the cation in 

56 is relatively kinetically slow,thus suggesting an intramolecular 

process. [178] 

Pseudorotaxanes—supramolecular complexes in which a 

macrocyclic host encapsulates a linear,threadlike guest—are 

subject to the same issues regarding kinetic stability as other 

host–guest complexes. [179–181] While these complexes are 

model systems for kinetically locked analogues (rotaxanes, [182] 

see Section 4),their dynamic properties are similar to other 

supramolecular systems. Many interesting pseudorotaxane 

devices have been created [183] with functions including: 

reversible formation and dethreading by using a number of 

stimuli; [122,123d,184] 

switching between different preferred 

guests; [185] shuttling between two binding sites within the 

same guest; [186] and control of intracomplex electron-transfer 

reactions. [187] However,only in the case of kinetically stable 

pseudorotaxanes—systems where the components do not 

exchange with the bulk during the operation of the machine— 

are there sufficient restrictions on the motions of the unbound 

species for them to feature controlled mechanical behavior 

and they are otherwise best considered as supramolecular 

devices not mechanical machines. [188] 

4. Controlling Motion in Mechanically Bonded 

Molecular Systems 

4.1. Basic Features 


Chemie 

Catenanes are chemical structures in which two or more 

macrocycles are interlocked,while in rotaxanes one or more 

macrocycles are mechanically prevented from dethreading 

from a linear unit by bulky “stoppers” (Figure 19). [189] Even 

though their components are not covalently connected, 

catenanes and rotaxanes are molecules (not supramolecular 

complexes) as covalent bonds must be broken to separate the 

constituent parts. In these structures, [190] the mechanical bond 

severely restricts the relative degrees of freedom of the 

Figure 19. Schematic representations of: a) a [2]catenane and b) a 

[2]rotaxane. [192] The arrows show possible large-amplitude modes of 

movement for one component relative to another. In a [2]rotaxane (b), 

these are defined as I: translation and II: pirouetting. In a [2]catenane, 

(a), however, motion I can be considered as pirouetting of the blue 

ring around the orange one or, equally, translation of the orange ring 

around the blue one. 


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Reviews 

components in several directions,while often permitting 

motion of extraordinarily large amplitude in an allowed 

vector. This situation is in many ways analogous to the 

restriction of movement imposed on biological motors by a 

track [170] and is one reason interlocked structures continue to 

play a central role in the development of synthetic molecular 

machines. [191] 

The large-amplitude submolecular motions particular to 

catenanes and rotaxanes can be divided into two classes 

(Figure 19): pirouetting of the macrocycle around the thread 

(rotaxanes) or the other ring (catenanes) and translation of 

the macrocycle along the thread (rotaxanes) or around the 

other ring (catenanes). By analogy to the stereochemical term 

“conformation”,which refers to geometries that can formally 

be interconverted by rotating about 

covalent bonds,the relative positioning 

of the components in interlocked 

molecules (and supramolecular complexes) 

is often referred to as a “coconformation”. 

[142] 

For a long time,synthetic 

approaches to mechanically interlocked 

structures relied on statistical 

or lengthy covalent-directed 

approaches. [193] The development of 

supramolecular chemistry,however, 

allowed chemists to apply noncovalent 

interactions to synthesis,thus 

resulting in many template methods 

(“clipping” and “threading”) [194] 

to 

catenanes and rotaxanes being developed. 

[195] In such syntheses,noncovalent 

binding interactions between the 

components often “live-on” in the 

interlocked products. These can ultimately 

be manipulated to effect positional 

displacements of one component 

with respect to another. Much 

attention has been given to the submolecular 

motions within these structures 

at equilibrium. We shall briefly 

cover the inherent large amplitude 

motion in rotaxanes as it is instructive 

for the consideration of stimuliinduced 

control of motion in these 

structures (see Sections 4.3–4.6). 

4.2. Shuttling in Rotaxanes: Inherent 

Dynamics 

Shuttling is the movement of a macrocycle along the 

linear thread component of a rotaxane. This motion takes the 

form of a random walk powered by Brownian motion that is 

constrained to one dimension by the thread and to translational 

displacement boundaries by the bulky stoppers. By 

virtue of the template methods employed in interlocked 

molecule synthesis, [195] rotaxanes without sites of attractive 

interaction between the macrocycle and thread are relatively 


rare. [196] It is more common that the thread consists of one or 

more recognition elements,or “stations”,for the macrocycle(s); 

shuttling therefore becomes the movement on,off, 

and between such stations,with rates dependent on the 

strength of the intercomponent interactions. 

4.2.1. Observation of Shuttling in Degenerate, Two Binding Site 

Molecular Shuttles 

Stoddart and co-workers demonstrated that 57 4+ ,the first 

[2]rotaxane to be constructed with two well-defined noncovalent 

binding sites,exhibits shuttling behavior (Scheme 

29a). [197] 1 H NMR experiments were consistent with the 

macrocycle moving between the two hydroquinol stations in 

Scheme 29. a) The first “molecular shuttle” 57 4+ . [197] b) Peptide-based degenerate molecular 

shuttles 58–61. [199] 

a temperature-dependent fashion. Directly analogous situations 

have subsequently been demonstrated for many rotaxanes 

bearing the same,or similar,macrocycles and multiple 

electron-rich aromatic rings on the thread. [198] 

Similar effects are seen with other multistation rotaxane 

systems. Shuttling dynamics have been systematically studied 

for a series of peptide-based molecular shuttles in which two 

glycylglycine stations are separated by aliphatic linkers. [199] In 

CDCl 3,the macrocycle in 58–60 shuttles between the two 

degenerate peptide stations rapidly at room temperature 

(Scheme 29b). The shuttling mechanism—a simplified profile 

is shown in Figure 20—requires at least partial rupture of the 

intercomponent interactions at one station before formation 



Figure 20. Idealized free-energy profile for movement 

between two identical stations in a degenerate 

molecular shuttle. The height of the barrier DG ° 

contains two components: the energy required to 

break the noncovalent interactions holding it to the 

station and a distance-dependent diffusional component. 

of new interactions at a second station. If the 

kinetic barrier can be made to be significantly 

larger than the available thermal energy,the 

shuttling will stop. This can be achieved for 60 

by introduction of a bulky N-tosyl (NTs) 

moiety (giving 61,Scheme 29b). Shuttling is 

restored upon removal of the N-tosyl barrier. 

In single binding site rotaxanes,hydrogenbond-disrupting 

solvents such as [D 6]DMSO 

break up the interactions between the benzylic 

amide macrocycle and peptide units, [200] 

and solvent composition indeed has a profound 

effect on the shuttling rate in 58–60.As 

little as 5% [D 4]methanol increases the 

shuttling rate by more than two orders of 

magnitude in halogenated solvents. [199,201] In a 

different hydrogen-bonded system,the shuttling 

rate could be controlled by deprotonation 

of a phenol moiety located between two 

degenerate stations. [202] Noncovalent interaction 

between the phenolate and counterion 

was found to significantly slow—but not 

prevent—shuttling,while the precise rate 

could again be fine-tuned by variation of the 

solvent composition. 

The reversible introduction of large 

kinetic barriers to shuttling has also been 

achieved without formation of covalent 

bonds. [203] In rotaxane 62,the crown ether 

normally shuttles between the two bipyridinium 

stations (Scheme 30). The introduction 

of Cu I ions,however,forms a kinetically stable dimeric 

complex,thus blocking movement of the ring. An ionexchange 

resin can be used to sequester the metal and restore 

shuttling. [204] 

4.2.2. A Physical Model of Degenerate, Two Binding Site 



Chemie 

An interesting structural effect is observed on increasing 

the length of the spacer in degenerate shuttles. Although 

ostensibly not involved in any interactions with the macrocycle,extension 

of the alkyl chain from 58 to 59 (Scheme 29b) 

reduces the rate of shuttling by a factor corresponding to an 

increase in activation energy of 1.2 kcalmol 1 —an effect 

solely of the increased distance the macrocycle must 

Scheme 30. Switchable degenerate shuttling through reversible formation of kinetically stable 

dimeric complexes. [204a] 


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Reviews 

travel. [199] This effect is most clearly understood by considering 

the macrocycle as a particle moving along a one-dimensional 

potential energy (rather than free-energy) surface 

(Figure 21). At any point on the potential-energy surface,the 

gradient of the line gives the force exerted on the macrocycle 

by the thread. When the macrocycle is in the vicinity of a 

station,hydrogen bonds and/or other attractive noncovalent 

interactions exert large forces (typically varying as a high 

power of the inverse distance r n ) on the macrocycle, 

opposing its motion. When the macrocycle is on the thread 

between the stations,the hydrogen bonds and other noncovalent 

binding interactions are broken and no forces are 

exerted on the macrocycle by the thread (that is,the gradient 

of the line is zero). The rate at which the macrocycles escape 

from each station is given by a standard Arrhenius equation, 

which depends on the depth of the energy well and the 

temperature. However,this is not the only factor involved in 

determining the rate at which macrocycles move between the 

two stations; there must also be some distance-dependent 

diffusional factor in the function describing rate of shuttling 

(Figure 21). 

The experimentally determined values of DG ° for 58 and 

59 have also been reconciled with a quantum-mechanical 

description of the shuttling process. [205] Calculation of the 

wavefunctions for the system shows that an increase in 

distance between the stations does not,of course,change the 

activation energy for cleavage of hydrogen bonds but rather 

the effect is to widen the free-energy potential well 

(Figure 20). As the well widens,it possesses a higher density 

of states per unit energy (just like the simple “particle-in-abox” 

model). The closer the levels are to one another,the 

more readily thermally populated they are or,in other words, 

the larger is the partition function and therefore also the 

DG ° value. 

Figure 21. Idealized potential energy of the macrocycle in a two-station, degenerate molecular shuttle. The 

potential-energy surface shows the effect of the interaction between the macrocycle and thread on the 

energy of the macrocycle (ignoring any complicating factors such as folding). Chemical potential energies 

(DE values) generally follow similar trends to free energies (DG values, Figure 20) but there are some 

important differences; for example, the activation free energy of shuttling DG ° corresponds to the energy 

required for the macrocycle to move all the way to the new binding site (that is, it includes a contribution 

for the distance the ring has to move along the track to reach the other station) whereas DE ° (shown here) 

represents the energy required for the macrocycle to escape the forces exerted through noncovalent binding 

interactions at a station. The main plot shows the DE value in terms of the position of the macrocycle along 

the vector of the thread; the minor plot shows the DE value in terms of the position of the macrocycle 

orthogonal to the vector of the thread, thus illustrating that the thread genuinely behaves as a onedimensional 

potential-energy surface for the macrocycle. 


The nature of the wavefunctions at energies close to the 

top of the barrier is intriguing,as under this energy regime the 

maximum probability of finding the macrocycle is over the 

aliphatic spacer. The shuttling process can therefore be 

thought of in terms of a function of free energy (Figure 20) 

as long as we remember that the height of the DG ° barrier is 

affected by both binding strength and distance between the 

stations. The behavior of the macrocycle is similar to a cart 

moving along a roller coaster track shaped like the double 

potential minima in Figure 20. At low temperatures,the cart 

mostly resides on the stations (oscillating with small amplitude 

in the troughs). As energy approaches the value of the 

barrier,the cart spends most of its time passing over the 

barrier (occupying co-conformations close to the transition 

state for movement between the stations). At higher energies 

still,the cart is most likely to be found at the extremes of its 

translational motion (once again occupying ground-state coconformations 

at the stations). 

4.3. Stimuli-Responsive Molecular Shuttles: Translational 

Molecular Switches 

As we have seen,the rate at which the macrocycle moves 

between the stations by Brownian motion in molecular 

shuttles can be regulated by temperature and,in some 

cases,solvent composition or binding events. However,the 

principle of detailed balance (Section 1.4.1) tells us that no 

useful task can be performed by such a process,even if the two 

stations are different. A more important kind of control is one 

in which the net location of the macrocycle is changed in 

response to an applied stimulus. This breaks detailed balance 

and,as the system relaxes back to equilibrium,the biased 

Brownian motion of the macrocycle can be used to perform a 

mechanical task. [206] 

4.3.1. Single Binding Site, Stimuli- 

Responsive Molecular Shuttles 

A limited amount of control over 

the position of the macrocycle can be 

introduced into single recognition site 

rotaxanes if the binding affinity can be 

affected by a stimulus. An important 

first step towards photoswitchable 

molecular shuttles was [2]rotaxane 

63 4+ (Scheme 31). [207] This rotaxane is 

closely related to 57 4+ ,but in 63 4+ 

there is only one electron-rich station 

for the macrocycle and the bulky 

stoppers are redox-active ferrocene 

groups. A laser flash photolysis pulse 

within the charge transfer band of 

63 4+ induces electron transfer from 

the dioxyarene to the cyclophane, 

thereby generating an intimate radical 

ion pair. Charge recombination is 

normally fast compared with any 

competing processes such as solvent 



Scheme 31. Conformational dynamics and electron-transfer processes possible in [2]rotaxane 63 4+ : a “single-station” molecular shuttle. [207] 

penetration or spatial separation of the radical ions. The 

flexible thread,however,allows close contact of the electronrich 

ferrocenyl stoppers with the cyclophane through a 

secondary p-stacking interaction (also observed in the solid 

state). This electronic coupling allows some of the radical ion 

pairs (ca. 25%) to undergo a secondary electron-transfer step 

in which the electron hole is transferred to one of the 

ferrocenyl stoppers. The interactions between the cyclophane 

and the stopper are therefore “switched off” and the molecule 

unravels. This spatially remote charge-separated state is 

relatively long-lived,so that some shuttling of the cyclophane 

away from the oxidized stopper may occur,driven by 

electrostatic repulsion. However,there is no direct evidence 

for this transient shuttling,or means to control the position of 

the cyclophane in the spatially remote charge-separated state. 

The environment-sensitive nature of the intercomponent 

hydrogen bonds in peptidic [2]rotaxanes allows control over 

effects arising from communication between the thread and 

macrocycle (Scheme 32a). Unlike the free sarcoglycine 

thread,rotaxane 64 exhibits only one (E) tertiary amide 

rotamer in apolar solvents,as the Z rotamer allows the 

formation of fewer favorable intercomponent hydrogen 

bonds (Scheme 32a). In hydrogen-bond-competing solvents, 

however,the interactions between the thread and macrocycle 

are “switched off” and both rotamers are observed. [208] It was 

found that a similar effect could switch on and off an induced 

circular dichroism (ICD) response between the intrinsically 

achiral benzylic amide macrocycle and the chiral center in the 

thread in chiral dipeptide [2]rotaxane 65 (Scheme 32b). [209] 

In two related systems,it has been possible to control the 

position of a cyclodextrin (CD) macrocycle on threads 

containing azobenzene and stilbene units (Scheme 33). [210,211] 

The cyclodextrin spends most of its time over the central 

aromatic units in the E isomers of [2]rotaxanes 66 and 67 in 

aqueous media. Irradiation at suitable wavelengths results in 

photoisomerization of the N=N and C=C bonds in 66 and 67, 

respectively,to the Z forms. The steric demands of the 

“kinked” thread require the cyclodextrin to be positioned 

away from the central unit. Even in the E isomers,however, 

the cyclodextrin does not sit exclusively over the central unit. 

This is in fact crucial for allowing photoisomerization to 

occur—an analogue of 66 which lacks the ethylene spacer 

(light blue) between the azobenzene and viologen units 

undergoes no photoisomerization as the trans chromophore is 

fully encapsulated by the ring. [210b,212] Interestingly,in 67, 

despite having a symmetrical thread,the displacement has 

been shown to be unidirectional,with the narrower 6-rim of 

the cyclodextrin always closest to the Z olefin. [211,213] It has 

been noted in a variety of studies that the asymmetry of 

cyclodextrins can result in the selective formation of orientational 

isomers when constructing pseudorotaxane or rotaxane 

architectures. [214] Although the observation of such isomers 

requires nonsymmetrical thread portions,an asymmetric 

substrate,such as a cyclodextrin ring,should itself satisfy 

the requirement of symmetry breaking for the creation of a 

full ratchet mechanism even on a symmetric track (see 

Section 1.4.2). 

4.3.2. A Physical Model of Two Binding Site, Stimuli-Responsive 



Chemie 

Rotaxanes in which the macrocycle can be translocated 

between two or more well-separated stations in response to 

an external signal should,in principle,provide a greater level 


105

Reviews 

Scheme 32. Environment-sensitive communication between interlocked components in single-station dipeptide [2]rotaxanes. a) In C 2D 2Cl 4, 

hydrogen bonding between the thread and macrocycle stabilizes the E rotamer so that this is the sole conformation observed by NMR 

spectroscopy. In [D 6]DMSO, the hydrogen bonding is switched off and both rotamers are observed, as they are for the free thread in all 

solvents. [208] b) In CHCl 3, the achiral macrocycle is held close to the chiral center, thereby conferring a chiral nature on its conformation which, in 

turn, affects the conformation of the C-terminal diphenylmethyl moiety, thus resulting in an ICD response. In MeOH, the hydrogen bonding is 

switched off and the communication between the components is lost. [209] 

Scheme 33. Photoresponsive single-station shuttles 66 [210] and 67, [211] based on azobenzene and 

stilbene units, respectively. 

of positional control. As seen in Section 4.2.2,in any rotaxane 

the macrocycle distributes itself between the available binding 

sites according to the difference in the macrocycle binding 

energies and the temperature. If a suitably large difference in 

macrocycle affinity exists between two stations,the macrocycle 

resides overwhelmingly in one positional isomer or coconformation. 

[142] In stimuli-responsive molecular shuttles,an 

external trigger is used to chemically modify the system and 

alter the noncovalent intercomponent interactions such that 

the second macrocycle binding site becomes energetically 

more favored,thus causing translocation of the macrocycle 


along the thread to the second 

station (Figure 22). This may be 

achieved by addressing either of 

the stations (destabilizing the initially 

preferred site or increasing the 

binding affinity of the originally 

weaker station). The system can be 

returned to its original state by using 

a second chemical modification to 

restore the initial order of station 

binding affinities. Performed consecutively,these 

two steps allow the 

“machine” to carry out a complete 

cycle of shuttling motion. 

The physical basis for this 

motion is again best understood by 

consideration of the potential 

energy of the macrocycle as a function 

of its position along the thread 

(Figure 23). It is important to appreciate that the external 

stimulus does not actually induce directional motion of the 

macrocycle,rather the system is put out of co-conformational 

equilibrium by increasing the binding strength of the lesspopulated 

station and/or destabilizing the initially preferred 

binding site. [215] Relaxation towards the new global energy 

minimum subsequently occurs by thermally activated motion 

of the components,a phenomenon which is recognized as 

biased Brownian motion. This effect can be envisaged as a net 

directional transport (a directional flux) of macrocycles 

towards the newly preferred station. 



Figure 22. Translational submolecular motion in a stimuli-responsive 

molecular shuttle: a) the macrocycle initially resides on the preferred 

station (orange); b) a reaction occurs (blue!green) which changes 

the relative binding potentials of the two stations such that, c) the 

macrocycle “shuttles” to the now-preferred station (green). If the 

reverse reaction (green!blue) now occurs (d), the components return 

to their original positions. 

Figure 23. Idealized potential energy of the macrocycle in a stimuli-responsive molecular shuttle in which 

one station changes (A’!A) in response to the stimulus and complicating factors such as folding are 

ignored. As before (Figure 21), the potential-energy surface shows the effect of the interaction between the 

macrocycle and thread on the energy of the macrocycle. The main plot shows the potential energy in terms 

of the position of the macrocycle along the vector of the thread; the minor plot shows the potential energy 

in terms of the position of the macrocycle orthogonal to the vector of the thread. 

Given this mode of action,a key requirement is finding 

ways of generating large long-lived binding energy differences 

between pairs of positional isomers. A Boltzmann distribution 

at 298 K requires a DDE (or DDG) value between 

translational co-conformers of about 2 kcalmol 1 for 95% 

occupancy of one station. Achieving such discrimination in 

two states to form a positionally bistable shuttle (that is,both 

DDE A’-B and DDE B-A 2 kcalmol 1 ) by modifying only 

intrinsically weak,noncovalent binding modes thus presents 

a significant challenge. 

4.3.3. Adding and Removing Protons to Induce Net Positional 

Change 

The first bistable switchable molecular shuttle,reported 

by Stoddart,Kaifer,and co-workers in 1994 and arguably the 

first true example of a molecular Brownian motion machine, 


Chemie 

employed a two-station design (Scheme 34). [216] The biphenol 

and benzidine units in the thread of [2]rotaxane 68 4+ are both 

potential p-electron-donor stations for the cyclobis(paraquatp-phenylene) 

(CBPQT 4+ ) cyclophane,and at room temperature 

rapid shuttling of the macrocycle occurs as in related 

degenerate shuttles (Section 4.2.1). Cooling the solution to 

229 K allowed observation (by NMR and UV/Vis absorption 

spectroscopy) of the two translational isomers in a ratio of 

21:4 in favor of encapsulation of the benzidine station. 

Protonation of the benzidine residue with CF3CO2D destabilizes 

its interaction with the macrocycle so that it now 

resides overwhelmingly on the biphenol station. The system 

can be restored to its original state by neutralization with 

[D5]pyridine. [217] 

Although this system is a controllable molecular shuttle,it 

exhibits modest positional integrity in the nonprotonated 

state—a much larger binding 

difference between the two 

stations is required. Inspired 

by the complexation of ammonium 

ions by crown 

ethers,a new series of rotaxanes 

based on threads containing 

secondary alkylammonium 

species and crown 

ether macrocycles was developed. 

[218] 

[2]Rotaxane 

[69·H] 3+ 

(Scheme 35) was 

the first switchable molecular 

shuttle reported using 

these units. [219] The dibenzocrown 

ether is bound to the 

ammonium cation by means 

of N + H···O hydrogen bonds 

as well as weaker C H···O 

bonds from methylene 

groups in the a position to 

the nitrogen atom. 1 H NMR 

spectroscopic analysis of the 

rotaxane in [D 6]acetone at 

room temperature shows (to 

the limits of detection of this 

experimental technique) the crown ether to be sitting mainly 

(but not exclusively [220] ) over the ammonium ion. Deprotonation 

of the ammonium center with diisopropylethylamine 

turns off the interactions holding the macrocycle to this 

station so it resides on the alternative bipyridinium station 

(69 2+ ). [221] A kinetic study of the shuttling in a closely related 

rotaxane revealed that the base-induced step is significantly 

slower than the return motion. This occurs despite a lower 

enthalpy of activation for the forward step and is due to 

entropic factors arising from the rearrangement of counterions 

in the transition state. [219c,222] 

While this example exhibits good macrocycle positional 

integrity in both chemical states,the low binding constant 

between the crown ether and bipyridinium moieties in the 

deprotonated state might be a limitation in more complex 

systems,especially if the macrocycle is afforded a greater 

degree of translational freedom (the distance between the 


107

Reviews 

Scheme 34. The first switchable molecular shuttle 68 4+ /[68·2 H] 6+ . [216] The macrocycle 

distribution in 68 4+ was determined by 1 H NMR spectroscopy at 229 K in 

CD 3CN. The macrocycle distribution in [68·2H] 6+ is based on the lack of 

observation of the other translational isomer by 1 H NMR spectroscopy at a 

number of temperatures in the range 193–304 K in [D 6]acetone 

stations in the current system is ca. 7 Š). Accordingly, 

Stoddart,Balzani,and co-workers prepared a combination 

of three shuttle units in parallel by using this system. [223] The 

molecule ([70·3 H] 9+ ,Scheme 36) consists of three threadlike 

components connected at one end and encircled by three 

catechol-polyether macrocycles connected in a platformlike 

fashion. Essentially,the shuttling action works as in 69; just 

over three equivalents of base are required to move the 

platform from the ammonium (“top”) to the bipyridinium 

(“bottom”) positions. Titration experiments and molecularmodeling 

studies indicate that the shuttling motion proceeds 

in a stepwise fashion with each polyether macrocycle stepping 

individually from station to station. The effect of combining 

the three binding sites is excellent positional integrity in both 

the fully protonated and fully deprotonated states,while a 

further analogue utilizing a dioxynaphthalene trismacrocyclic 

platform exhibits even stronger interactions when on the 

bipyridyl station. [223b] 

The first pH-switchable shuttle to exploit hydrogenbonding 

interactions to anions was recently reported. [224] In 

[2]rotaxane 71·H (Scheme 37) formation of the benzylic 

amide macrocycle is templated by a succinamide station in 

the thread. However,the thread also contains a cinnamate 

derivative. In the neutral form the macrocycle resides on the 


succinamide station more than 95% of the time 

because the phenol ring is a poor hydrogenbonding 

group. Deprotonation in [D 7]DMF to 

give 71 results in the macrocycle changing 

position to bind to the strongly hydrogen-bondbasic 

phenolate anion. Reprotonation returns the 

system to its original state and the macrocycle to 

its original position. However,the shuttling is 

extremely solvent-dependent. Hydrogen-bonding 

molecular shuttles usually perform best in “noncompeting” 

solvents. However,when the deprotonation 

of 71·H is carried out in CDCl 3 or 

CD 2Cl 2,a change of position of the macrocycle 

does not occur. Instead,intramolecular folding 

occurs to allow the phenolate group to hydrogen 

bond with the macrocycle while it remains on the 

succinamide station. This solvent dependence is 

explained by the fact that the phenolate group can 

only satisfy the hydrogen-bonding requirements 

of one isophthalamide unit of the macrocycle. The 

DMF facilitates shuttling by hydrogen bonding to 

the remaining amide groups of the macrocycle. 

Shuttling is unaffected by the nature of the 

accompanying cation or the addition of up to ten 

equivalents of other anions. 

Scheme 35. A pH-responsive bistable molecular shuttle displaying 

good positional integrity in both chemical states. [219] Statistical 

distributions of the macrocycle were determined at a number of 

temperatures in the range 193–304 K in [D 6]acetone. 



Scheme 36. Chemical structure of a “molecular elevator” [70·3H] 9+ /70 6+ . [223] 

Scheme 37. pH-switched anion-induced shuttling in hydrogen-bonded 

[2]rotaxane 71·H/71 in [D 7]DMF at RT. [224] Bases that are effective 

include LiOH, NaOH, KOH, CsOH, Bu 4NOH, tBuOK, DBU, and 

Schwesinger’s phosphazine P 1 base, thus illustrating the lack of 

influence of the accompanying cation on shuttling. 

4.3.4. Adding and Removing Electrons To Induce Net Positional 

Change 

In the original switchable shuttle 68 4+ (Scheme 34),the 

change of position could also be achieved in a reagent-free 

manner by electrochemical oxidation of the benzidine 

station; the macrocycle shuttles away from this station after 

oxidation to the radical cation. [216] A number of attempts to 


Chemie 

create related redox-switched shuttles with greater positional 

integrity failed to give an improved distribution of translational 

isomers in the ground state. [225,226] Incorporation of 

redox-active stations based on tetrathiafulvalene (TTF), 

however,has given rise to a whole series of redox-active 

shuttles,a typical example of which (72 4+ /72 6+ ) is illustrated in 

Scheme 38. [227] Switching of the CBPQT 4+ cyclophane 

between TTF (or closely related derivatives) and dioxyarene 

units has since been extensively studied in both rotaxane and 

catenane (see Section 4.6.1) architectures (as well as a 

number of model systems) to fully understand the relationship 

between chemical structure and performance characteristics 

with a view to incorporate these shuttles in various 

condensed-phase devices (see Section 8.3). [180c,184l,u,186c,227,228] 

One of the key findings to emerge from these studies is that 

there is a significant activation barrier for the shuttling of the 

ring back onto the TTF unit when it is reduced from the 

oxidized state. This is in contrast to movement away from the 

freshly oxidized TTF unit which involves a very low kinetic 

barrier on account of the unfavorable interaction between the 

two positively charged components. The metastable state can 

be observed in solution at low temperature, [228f] and its 

characterization has been crucial in determining the mechanism 

of operation of the solid-state electronic devices 

constructed from molecules of this type (see Section 8.3.1). 

An electrochemical switch with one of the highest 

positional fidelities (ca. 10 6 :1 in one state; ca. 1:500 in the 

other) has been demonstrated with amide-based molecular 

shuttles. [229] [2]Rotaxane 73 contains two potential hydrogenbonding 

stations (a succinamide (succ) station and a redoxactive 

3,6-di-tert-butyl-1,8-naphthalimide (ni) station) for the 

benzylic amide macrocycle that are separated by a C 12 

aliphatic spacer (Scheme 39). [229] 

While the ability of the succ station to template formation 

of the macrocycle is well established,the neutral naphthalimide 

moiety is a poor hydrogen-bond acceptor. In fact,the 


109

Reviews 

Scheme 38. Redox-switchable molecular shuttle 72 4+ /72 6+ . [227] The redox reactions may be carried out either chemically or electrochemically. 

Scheme 39. A photochemically and electrochemically switchable, hydrogen-bonded 

molecular shuttle 73. [229] In the neutral state, the translational co-conformation succ- 

73 is predominant as the ni station is a poor hydrogen-bond acceptor 

(K n = (1.2 1) ” 10 6 ). Upon reduction, the equilibrium between succ-73 C and 

ni-73 C is altered (K red = (5 1) ” 10 2 ) because ni C is a powerful hydrogen-bond 

acceptor and the macrocycle moves through biased Brownian motion. Upon 

reoxidation, the macrocycle shuttles back to the succinamide station. Repeated 

reduction and oxidation causes the macrocycle to shuttle forwards and backwards 

between the two stations. All the values shown refer to cyclic voltammetry experiments 

in anhydrous THF at 298 K with tetrabutylammonium hexafluorophosphate 

as the supporting electrolyte. Similar values were determined on photoexcitation 

and reduction of the ensuing triplet excited state by an external electron donor. 


difference in macrocycle binding affinities is so great that 

succ-73 is the only translational isomer detectable by 

1 H NMR specroscopy in CDCl3,CD 3CN,and [D 8]THF (an 

equilibrium constant of (1.2 1) ” 10 6 for the two translational 

isomers was determined by electrochemistry in 

THF containing Bu 4NPF 6 as a supporting electrolyte); 

even in the strongly hydrogen-bond-disrupting 

[D 6]DMSO,the macrocycle resides over the succ station 

about half of the time. One-electron reduction of naphthalimide 

to the corresponding radical anion,however, 

results in a substantial increase in electron charge density 

on the imide carbonyl groups and a concomitant increase 

in hydrogen-bond-accepting ability. In 73,this reverses the 

relative hydrogen-bonding abilities of the two thread 

stations so that co-conformation ni-73 C is preferred over 

succ-73 C to the extent of approximately 500:1. Subsequent 

reoxidation to the neutral state restores the original 

binding affinities and the shuttle returns to its initial 

state. The process can be observed in cyclic voltammetry 

experiments, [229b] or alternatively photochemistry can be 

employed to initiate (through excitation of the naphthalimide 

group by a nanosecond laser pulse at 355 nm 

followed by electron transfer from an external electron 

donor) and observe (by using transient absorption spectroscopy) 

the change of position. [229a] Importantly,a 

number of control experiments involving the incorporation 

of steric barriers to shuttling were carried out to prove 

unequivocally that the dynamic process observed in this 

rotaxane system is a reversible shuttling of the macrocycle 

between the stations rather than any other conformational 

or co-conformational changes. [229b,230] 

Although many metal–ligand interactions can be 

rather kinetically stable,the difference in preferred 

coordination geometries of different oxidation states can 

be exploited to bring about redox-induced shuttling in 

transition-metal-based systems. The preference of Cu I ions 

for four-coordinate tetrahedral complexes has been widely 

employed in the synthesis of interlocked architectures, [189- 



g,195a,e–g,j,af] 

as it enforces the orthogonal arrangement of two 

bidentate ligands which can be further elaborated to give 

rotaxanes or catenanes. In [Cu I (74)] (Scheme 40),a macrocycle 

containing a bidentate 2,9-diphenyl-1,10-phenanthroline 

(dpp) unit,is locked onto a thread which contains one 

bidentate phenanthroline (phen) and one tridentate 2,2’:6’,2’’terpyridine 

(terpy) unit. [231] Chelation of Cu I ions ensures that 

the macrocycle is positioned over the phenanthroline station 

in the thread,phen-[Cu I (74)]. Electrochemical oxidation 

initially generates phen-[Cu II (74)]. However,as Cu II ions 

prefer higher coordination numbers,a thermally activated 

relaxation to the thermodynamically preferred terpy- 

[Cu II (74)] occurs. The metastable phen-[Cu II (74)] state is 

relatively kinetically inert,however,and this shuttling step 

takes several hours at room temperature (k = 1.5 ” 10 4 s 1 ). 

Electrochemical reduction of the divalent species gives terpy- 

[Cu I (74)] which slowly converts into the original translational 

isomer phen-[Cu I (74)] (10 4 

k 10 2 s 1 ,which is slightly 

faster than the first step because of the smaller charge on the 

metal center). The same shuttling process can also be 

accomplished by a photochemically triggered oxidation. The 

reverse reduction step cannot be carried out photochemically 

but proceeds successfully with a chemical reductant (ascorbic 

acid). [232] 

Scheme 40. Redox-switched shuttling in the metal-templated [2]rotaxane 74. [231] 


Chemie 

4.3.5. Adding and Removing Metal Ions To Induce Net Positional 

Change 

The research groups of Sanders and Stoddart have 

collaborated to produce another class of molecular shuttles 

that can be switched in several ways (Scheme 41). In the 

ground state,the co-conformation of kinetically stable 

[2]pseudorotaxane 75 with the macrocycle sitting over the 

naphthaldiimide station (blue) is dominant,as observed by 

1 H NMR spectroscopy and one-electron reduction of this 

station (which has the lower reduction potential) results in 

shuttling of the ring onto the pyromellitic diimide station 

(green). Somewhat unexpectedly,however,the change in 

position of the macrocycle can also be induced by adding 

lithium ions. Two of the small metal ions can be complexed 

between the crown ether macrocycle and the carbonyl groups 

of the diimide moieties and this interaction is significantly 

stronger at the pyromellitic station (Scheme 41). Addition of 

a large excess of [18]crown-6 sequesters the lithium ions, 

thereby returning the system to its initial state. [233] 

Rather than serving to enhance intercomponent interactions 

at a specific station,metal-ion binding can be used to 

destabilize the binding of the macrocycle at one site,thus 

causing it to translocate to another,unaffected unit. This is 


111

Reviews 

Scheme 41. Cation-induced shuttling based on complexation and decomplexation of lithium ions. [233] 

possible through two distinct mechanisms (Scheme 42). [234,235] 

In [2]rotaxane 76 the macrocycle preferentially sits over the 

glycylglycine station derivatized with a bis(2-picolyl)amino 

(BPA) stopper. The addition of one equivalent of Cd- 

(NO3) 2·4 H2O generates a complex in which the metal ion is 

bound to the first carboxamide carbonyl oxygen atom as well 

as the three nitrogen donors of the BPA ligand,and the 

preferred postion of the macrocycle remains essentially 

unchanged. However,deprotonation of the first carboxamide 

moiety [236] results in coordination of the nitrogen anion,as 

well as the carbonyl oxygen atom of the second carboxamide 

group. The cadmium ion essentially wraps itself up in the 

deprotonated glycylglycine residue,thus switching off any 

intercomponent interactions with the macrocycle which now 

occupies the succinic amide ester station. The shuttling 

process is fully reversible: removal of the Cd II 

ion with 

excess cyanide and reprotonation of the amide nitrogen atom 

with NH4Cl quantitatively regenerates 76. [234] In [2]rotaxane 

77,again the macrocycle preferentially resides on the 

carboxamide-based station adjacent to a BPA ligand. In this 

case,divalent metal ions such as Cd II are only able to chelate 

to the three BPA nitrogen atoms. To accommodate such a 

binding mode,however,the two pyridyl arms must adopt a 

coplanar conformation,which sterically destabilizes macrocycle 

binding to the succinamide station,thus causing it to 

move to the inherently weaker succinic amide ester unit. 

Rather than competing for the same donor atoms,as in 76,the 

metal- and macrocycle-binding modes in 77 compete for the 

same 3D space so that this mechanism corresponds to a 

negative heterotropic allosteric binding event. The shuttling is 

fully reversible on demetalation of [Cd(NO3) 2(77)] with 

cyanide. [235] 


4.3.6. Adding and Removing Covalent Bonds To Induce Net 

Positional Change 

Perhaps surprisingly,the use of covalent-bond-forming 

reactions to bring about positional change in molecular 

shuttles has not yet been explored extensively. In one 

successful example,the formation (and breaking) of C C 

bonds through Diels–Alder and retro-Diels–Alder reactions 

of rotaxane 78 (Scheme 43) can control shuttling with 

excellent positional discrimination: the steric bulk of the 

Diels–Alder adduct displaces the macrocycle to the succinic 

amide ester station in Cp-78. [237] 

A transient shuttling system involving photoinduced 

cleavage of a covalent bond and subsequent recombination 

has recently been reported. Diaryl cycloheptatrienes can act 

as p-electron-donor binding sites in rotaxanes containing 

CBPQT 4+ macrocycles. [180b,d] In [2]rotaxane 79 4+ ,the cationic 

cyclophane resides over the diarylcycloheptatriene station 

(green) with additional “alongside” interactions with the 

anisole unit (red). Photoheterolysis of the C OMe bond 

under conventional flash photolysis conditions at 360 nm 

generates the diaryl tropylium cation and displaces the ring to 

the anisole station (Scheme 44). The lifetime of this species at 

room temperature is 15 s,before the thermal back reaction 

returns the system to 79 4+ (or a regioisomer resulting from 

nucleophilic attack of the methoxide at a different site on the 

seven-membered ring). The shuttling motion was inferred by 

comparison of the transient absorption spectrum of 

79 5+ ·MeO with the spectral characteristics of 79 5+ generated 

by electrochemical oxidation. [238] Recently,modifications to 

the inactive thread components have allowed preparation of 

an analogue which adopts a linear conformation in the ground 



Scheme 42. a) Shuttling through stepwise competitive binding. [234] A 

similar shuttling mechanism can be observed with Cu II ions, where the 

deprotonation results in a color change. b) An allosterically regulated 

molecular shuttle. [235] 

Scheme 43. Shuttling through reversible formation of covalent 

bonds. [237] The absolute stereochemistry for Cp-78 is depicted 

arbitrarily. 

Scheme 44. Photoheterolysis-induced reversible shuttling through 

formation of a tropylium cation. [238] 


Chemie 

state and for which formation of the tropylium cation can be 

achieved with acids,as well as through the photoheterolysis 

mechanism. [239] 


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Reviews 

4.3.7. Changing Configuration To Induce Net Positional Change 

As with controlling motion in covalently bonded systems, 

isomerization processes,particularly photoisomerization processes,are 

a very attractive means of inducing shuttling in 

rotaxanes. Shuttle (E)/(Z)-80 (Scheme 45) utilizes the inter- 

Scheme 45. Bistable molecular shuttle (E)/(Z)-80 in which self-binding 

of the low affinity station in each state is a major factor in producing 

excellent positional discrimination. [240] Similar results are achieved 

when the intermediate affinity station (orange) is a succinic amide 

ester. 

conversion of fumaramide (trans) and maleamide (cis) 

isomers of the olefinic unit. [240] Fumaramide groups are 

excellent binding sites for benzylic amide macrocycles: [241] 

the trans olefin holds the two strongly hydrogen bond accepting 

amide carbonyl groups in a preorganized close-to-ideal 

spatial arrangement for interaction with the amide groups of 

the macrocycle. Although a similar hydrogen-bonding surface 

is presented to the host,binding of the macrocycle to the 

succinamide station in (E)-80 would result in a loss in entropy 

(loss of bond rotation in the succinamide group) as well as one 

less intracomponent hydrogen bond than would be present in 

the fumaramide-occupied positional isomer. The result is that 

only one major positional isomer of (E)-80 (shown in 

Scheme 45) is observed at room temperature in CDCl 3. 

Photoisomerization (254 nm) reduces the number of possible 

intercomponent hydrogen bonds at the olefin station from 

four to two and so the macrocycle changes position to the 

succinamide station ((Z)-80,Scheme 45). Unlike many other 

light-switchable shuttles,this new state is essentially indefinitely 

stable until a further stimulus is applied to reisomerize 

the maleamide unit back to fumaramide. 

4.3.8. Shuttling through Excited States 


When operating in the light-stimulated mode,[2]rotaxane 

73 (Section 4.3.4) employs a highly oxidizing photochemically 

excited state to trigger the electron-transfer process which 

results in macrocycle shuttling. After about 100 ms,the 

reduced rotaxane undergoes charge recombination with the 

radical cation of the external electron donor to regenerate the 

starting state. As long as photons of a suitable wavelength are 

supplied,this process will continue to occur indefinitely; the 

photochemical process can be said to be autonomous. The 

same principle is also true of shuttle 79 (Section 4.3.6). 

Attempts to induce shuttling using intramolecular electron 

transfer from photoexcited states have in the past been 

plagued by the problem of back electron transfer being fast 

compared to the desired nuclear motion. [207,232b] Recently, 

however,it has been demonstrated that a previously studied 

[2]rotaxane, 81 6+ , [232b] does indeed undergo shuttling in an 

intramolecular charge-separated state (Figure 24). [242,3] Irradiation 

of the ruthenium–trisbipyridine complex (green) 

generates a highly reducing excited state. An intramolecular 

electron transfer then occurs between the excited metal 

center and the most easily reduced bipyridinium station 

(blue),on which the macrocycle prefers to sit. The result is 

destabilization of the macrocycle–station interactions so that 

the alternative bipyridinium unit (pink) is now preferred. 

Remarkably,in this system the back electron-transfer process 

is slow enough to allow shuttling of the ring towards the other 

station in approximately 10 % of the molecules. Naturally, 

charge recombination quickly restores the initial state,but if 

photons are continually supplied,this cycle is followed 

indefinitely. 

In another example,shuttling has been observed simply as 

a result of the altered electron density in a photoexcited state, 

without any subsequent electron-transfer reactions. The nonplanarity 

of the anthracene-9-carboxamide unit in [2]rotaxane 

82 means the macrocycle can only form hydrogen bonds 

with one of the amide carbonyl groups (Scheme 46). [243] 

Photoexcitation of the anthracene system causes a planar 

conformation to be adopted in which some charge is transferred 

onto the adjacent carbonyl group,thus increasing its 

hydrogen-bond basicity. Subsequent translocation of the 

macrocycle occurs on a nanosecond timescale and is reflected 

in a change in the anthracene fluorescence spectrum,before 

decay of the excited state restores the original co-conformation. 

These shuttles operate without the consumption of 

chemical fuels or the formation of waste products and they 

automatically reset so that they operate autonomously. It 

must be noted,however,that if a continuous supply of 

photons is provided the distribution of the rings between the 

two stations would reach a steady state (the exact ratio 

depending on the intensity of the light) within a few milliseconds. 

For an autonomous molecular motor (for example, 

46; see Section 2.2) a steady state of isomer populations can 

still correspond to a net flux in a particular direction through 

these forms. In switches such as these shuttles,however,after 

the steady state has been reached,there is no subsequent net 

flux of rings between the two stations at any point in time. The 



Figure 24. Chemical structure (a) and operating cycle in a schematic form (b) of a molecular shuttle 81 6+ 

operating through a photoinduced internal charge-separated state. [242,3] At equilibrium in the ground state, 

the ring spends most of the time over the unsubstituted bipyridinium station (blue, A). Irradiation (1) of the 

ruthenium complex (green) generates a highly reducing excited state, which results in electron transfer (2) 

to the blue station, thus weakening its electrostatic interactions with the ring (B). Normally charge 

recombination processes such as (3) are fast in comparison with nuclear motions, but here it is slow 

enough to allow approximately 10 % of the molecules to undergo significant Brownian motion (4), thereby 

shifting the statistical distribution in this portion of the ensemble to favor the dimethylbipyridinium station 

(pink, C). When charge recombination (5) eventually does take place, the higher binding affinity of the blue 

station is restored (D). The system relaxes (6) to restore the original statistical distribution of rings (A). 

Scheme 46. Photoinduced shuttling in the singlet excited state of 

benzylic amide [2]rotaxane 82. [243] The shuttling amplitude is approximately 

3 Š and the lifetime of 82* is 4.3 ns. 

only way to generate net 

fluxes of macrocycles 

between the stations in 

these types of systems 

would be to rapidly switch 

the photon source on and 

off. [3] 

4.3.9. Entropy-Driven 

Shuttling 


Chemie 

Most of the shuttles 

which exhibit excellent positional 

discrimination 

between two stations are 

switched using stimuli to 

modify the enthalpy of the 

macrocycle binding to one or 

both stations. Generally,the 

effect of temperature is only 

to alter the degree of discrimination,not 

to alter the 

station preference. [244] 

In 

[2]rotaxane 83,however,the 

macrocycle can be switched 

between stations simply by 

changing the temperature. 

[245] In fact, 83 is a tristable 

molecular shuttle: the 

ring can be switched 

between three different positions 

on the thread 

(Scheme 47). 

Structurally, 83 is closely 

related to 80,the differences 

being substitution of the isophthaloyl 

unit in the macrocycle for pyridine-2,6-dicarbonyl 

groups and replacement of the succinamide station with a 

succinic amide ester. In the (E)-83 form,the macrocycle 

resides over the fumaramide station in CDCl 3 at all temperatures 

investigated. However,although the 1 H NMR spectrum 

of the maleamide isomer ((Z)-83) in CDCl 3 showed that 

the macrocycle was no longer positioned over the olefin 

station,the spectrum was highly temperature-dependent. At 

elevated temperatures (308 K) the expected succ-(Z)-83 coconformation 

was observed,but at lower temperatures it is 

the alkyl chain which exhibits the spectroscopic shifts 

indicative of encapsulation by the macrocycle (dodec-(Z)- 

83,Scheme 47). The origin of this temperature-switchable 

effect is the large difference in the entropy of binding 

(DS binding) to the succinamide and alkyl chain stations which 

allows the TDS binding term to have a significant impact on the 

DG binding value as the temperature is varied. [246] In the succ- 

(Z)-83 co-conformation,the macrocycle forms two strong 

hydrogen bonds with an amide carbonyl group and two, 

significantly weaker,bonds to the ester carbonyl group. The 

dodec-(Z)-83 co-conformation allows the formation of four 

strong hydrogen bonds to amide carbonyl groups,thus 

making it enthalpically favored by about 2 kcal mol 1 . At 


115

Reviews 

Scheme 47. A tristable molecular shuttle 83. [245] 

low temperatures,where the effects of entropy are less 

significant,the molecule adopts the dodec-(Z)-83 co-conformation. 

At higher temperatures,the increased contribution 

from the TDS binding term favors the entropically preferred 

succ-(Z)-83 co-conformation. [247] 

4.3.10. Shuttling through a Change in the Nature of the 

Environment 

A significant advantage [248] of using temperature to induce 

a change in net position of the macrocycle in a molecular 

shuttle is that no chemical reaction is involved and any 

property change associated with the new state cannot arise 

from a change in the covalent structure of the molecule. The 

same holds true for switching induced by a change in the 

nature (solvation or polarity) of the environment of the 

shuttle. The benzylic amide macrocycle in amphiphilic 

rotaxanes (including those discussed in Section 4.2.1) can be 

shuttled between various hydrogen-bonding stations (CDCl 3 

and most nonpolar solvents) and an alkyl chain ([D 6]DMSO, 

H 2NCHO). [199,249] A similar effect has been observed in a 

range of poly(urethane/crown ether rotaxane)s. [250] 

Many of the examples of stimuli-induced shuttling described 

in Sections 4.3.1–4.3.9 display remarkable degrees of 

control over the positioning and dynamics of submolecular 

fragments. They utilize a number of different stimuli-induced 

processes to trigger changes in the net position of macrocycles 

over large distances (up to ca. 15 Š in the case of 71, 73,and 

80) and operate over a range of timescales (a complete 

switching cycle in 73 is over in ca. 100 ms while,in 80,both 

states are effectively indefinitely stable). Note,however,that 

all these shuttles exist as an equilibrium of co-conformations 


and it is just the position of the 

equilibrium that is being varied. [220] 

As the position of equilibrium 

changes,detailed balance is broken 

and it is this that can allow a useful 

mechanical task to be performed by 

Brownian motion of the macrocycle. 

4.4. Compartmentalized Molecular 

Machines 

We discussed in Section 4.3.2 how 

stimuli-responsive molecular shuttles 

can be considered in terms of a 

machine (the thread) which transports 

a particle (the interlocked macrocycle) 

between two sites (compartments) 

on a one-dimensional potential-energy 

surface. This approach 

provides a basic framework with 

which to explore some of the ideas 

to create,control,order,and manipulate 

non-equilibrium conformations 

and co-conformations raised at the 

end of Section 1.4.2. In all of the 

examples in Section 4.3,an external 

stimulus alters the relative binding affinities of the stations for 

the macrocycle by placing the system momentarily out of coconformational 

equilibrium. Detailed balance is broken and 

the system acts to restore balance through biased Brownian 

motion of the macrocycles towards the new global minimum. 

Detailed balance,however,can be considered to result from 

two separate properties of the system (Section 1.4.1): the 

statistical distribution of a quantity (an imbalance which 

provides the thermodynamic impetus for net transport) and 

the ability of that quantity to be dynamically exchanged 

(which provides the communication necessary for transport to 

occur). [51] In the switchable shuttles of Section 4.3,the macrocycle 

is at all times able to seek its equilibrium statistical 

distribution along the full length of the thread,and the 

position of the substrate is always indicated by the state of the 

machine. To create artificial Brownian machines which are 

more sophisticated than simple positional switches,control 

over the kinetics for exchange of the substrate between two 

sites of the machine must be introduced. 

Rotaxane system 84 is able to change the average position 

of the macrocycle irreversibly through a fundamentally 

different mechanism to previous shuttles (Scheme 48). [32] In 

84 the two stations are structurally identical (but distinguishable: 

note the different stoppers) and a bulky silyl ether acts 

as a barrier which prevents the ring from moving between 

them. The system starts out statistically unbalanced (succ1-84, 

because of the synthetic route used to access it). The stimulus 

that leads to the net change in position of the macrocycle is a 

“linking” operation—removal of the silyl ether—which 

switches “on” dynamic exchange of the macrocycle between 

the two stations and allows the system to move towards 

equilibrium,which results in an average displacement of the 



Scheme 48. Operation of a compartmentalized Brownian 

molecular machine that acts as an irreversible switch. [32] As the 

macrocycle distributions on the thread are determined when 

the two compartments are unlinked, they are independent of 

factors such as temperature or solvent. TBDMS = tert-butyldimethylsilyl. 

macrocycle half the distance separating the two 

stations. This is a molecular-level form of “escapement”,the 

element of the mechanism that controls the 

release of potential energy to drive mechanical motion 

in clocks and other macroscopic mechanical devices. 

Raising the barrier by applying an “unlinking stimulus” 

resets the machine (the thread) without undoing 

the task just performed. However,applying the linking 

stimulus again after the machine is reset,does not 

change the average position of the macrocycle a 

second time,because the system is now statistically 

balanced. This stimuli-induced irreversible net change 

in the position of the macrocycle represents a new type 

of molecular shuttle in phenomenological terms: its 

operation is irreversible and the state of the machine 

(the thread) does not determine the position of the 

substrate. 

Combining control over exchange between the two 

stations (kinetics) with the ability to modulate their 

relative binding affinities (thermodynamics) led to the 

creation of another novel type of simple molecular 

machine system,namely 85 (Scheme 49). [32] Here,the 

machine is statistically balanced (85 % of the macrocycles 

on the fumaramide (green) station,15 % on the 

succinamide (orange) station),and unlinked (and 

therefore not in equilibrium) by simply removing and 

reattaching the silyl group (Scheme 49,steps a and c). 

From this balanced state,a balance-breaking stimulus 

is applied (irradiation at 312 nm,generating a 49:51 

2% E:Z photostationary state),followed by removal 

of the kinetic barrier (“linking stimulus”) which allows 

balance to be restored by biased Brownian motion of 


Chemie 

the ring towards the new equilibrium distribution. Restoring 

the barrier (“unlinking stimulus”) makes the system unlinked 

and not in equilibrium,although statistically balanced. The 

resetting step (a different balance-breaking stimulus,to 

promote the Z!E olefin isomerization),makes the system 

statistically unbalanced,unlinked,and not in equilibrium. 

After the operational cycle of the machine,approximately 

56% of the macrocycles are located on the succinamide 

station. The transportation of the macrocycle in 85 is 

repeatedly reversible between the statistically balanced 

(85:15) and statistically unbalanced (44:56) ratios of fum- 

(E)-85 to succ-(E)-85. 

In this rotaxane the thread performs the task of directionally 

changing the net position of the macrocycle—and 

since the succinamide station binds the macrocycle more 

weakly than the fumaramide station,the thread moves the 

macrocycle energetically uphill—while itself returning to its 

Scheme 49. Operation of compartmentalized molecular machine 85 which corresponds 

to a two-state Brownian flip-flop. [32] Operation steps: a) Desilylation (80% aqueous acetic 

acid); b) E!Z photoisomerization (hn at 312 nm); c) resilylation (TBDMSCl); and 

d) Z!E thermal isomerization (catalytic piperidine). As the macrocycle distributions on 

the thread are determined when the two compartments are unlinked, they are 

independent of factors such as temperature or solvent. 


117

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initial state. This behavior amounts to “ratcheting”,a 

characteristic feature of the operating mechanisms of many 

biological molecular machines. A thermodynamically unfavorable 

concentration gradient of the macrocycle between the 

compartments is the result,which is precisely the function 

envisaged for the thought-machine pressure demons discussed 

in Section 1.2.1. Unlike the thought machines,however,the 

position of the Brownian particle in 85 has no role in 

the mechanism. [251] Rather the rotaxane machine carries out a 

sequence of four steps (independent of the position of the 

particle) which govern in turn the thermodynamics and the 

kinetics for transport between the two stations (Figure 25): 

balance-breaking 1,linking,unlinking,balance-breaking 2 

(resetting,of the machine not the substrate). 

Figure 25. The operation [32] of machine–substrate system 85 in Scheme 49 is the experimental 

realization (albeit in non-adiabatic form) of the transportation task required of Smoluchowski’s 

trapdoor [16] (Figure 4a) and Maxwell’s pressure demon [15c] (Figure 2b). The mechanistic 

equivalent of the schematic representations from Section 1.4.2 is shown above. The colors of 

the compartments, particles, and door are the same as the corresponding elements of 85. 

The initially balanced (in proportion to the sizes of the two compartments) distribution of the 

Brownian particles between the left (L) and right (R) compartments becomes statistically 

unbalanced by a change in the volume of the left-hand compartment. Opening the door 

allows the particles to redistribute themselves according to the new size ratio of the 

compartments. Closing the door ratchets the new distribution of particles. Restoring the lefthand 

compartment to its original size then results in a concentration gradient of the 

Brownian particles across the two compartments. There is no role for an informationgathering 

demon in this mechanism. 

Significantly,examining the state of the machine (the 

rotaxane thread) in 85 does not provide information regarding 

the state (distribution) of the substrate. It is only from the 

history of the machine s operations that the distribution of the 

substrate can be known; in other words,the net position of the 

macrocycle in rotaxane 85 is a consequence of a form of 

sequential logic. [252] The behavior of 85 is characteristic of a 

two-state (one-bit) memory or “flip-flop” component in 

electronics [253] and therefore 85 is the first example of a new 

class of simple molecular machine: a two-state Brownian flipflop. 

A flip-flop maintains its effect on a system indefinitely 

until an input pulse operates on it that causes its output to 

change to a new indefinitely stable state according to defined 

rules. [254] 

From the analysis of the behavior of these rotaxanes,and 

the analysis of the workings of the fluctuation-driven transport 

mechanisms discussed in Section 1.4.2,there appear to 


be four phenomenological terms (ratcheting,escapement, 

balance,and linkage) that are crucial for controlling the nonequilibrium 

distribution of Brownian substrates with compartmentalized 

molecular-level machines: 

1) “Ratcheting” [32] 

is an often used,but previously illdefined,process 

in chemical terms. Unfortunately,this 

vagueness has led to the term sometimes being applied to 

describe phenomena that are unrelated to Brownian 

ratchet mechanisms. Ratcheting is the capturing of a 

positional displacement of a substrate through the imposition 

of a kinetic energy barrier which prevents the 

displacement being reversed when the thermodynamic 

driving force is removed. The key feature of ratcheting is 

that the ratcheted part of the system is not linked with 

(that is,not allowed to exchange the substrate 

with) any part of the system that it is ratcheted 

from. Ratcheting is a crucial requirement for 

allowing a Brownian machine to be reset 

without undoing the task it has performed; 

2) “Escapement” [32] is the counterpart to ratcheting 

and consists of the (directional) release of a 

ratcheted substrate in a statistically unbalanced 

system by lowering a kinetic energy barrier (by 

linking). The key feature of escapement is that 

it requires the linking of two unbalanced parts 

of a system that were previously unlinked. An 

escapement step must be subsequently ratcheted 

for a machine to be able to do work 

repetitively on a substrate; 

3) “Balance” [32,51] is the thermodynamically preferred 

distribution of a substrate over a 

machine or parts of a machine. The impetus 

for net transportation of a substrate between 

two parts of a machine comes from the balance 

being broken (note that balance being broken 

is not the same as detailed balance being 

broken,balance is the thermodynamic driving 

force for detailed balance); 

4) “Linkage” [32,51] is the communication necessary 

for transportation of a substrate to occur 

between parts of a machine. However,the 

ability to exchange the substrate between the 

linked parts is not in itself enough for a task to be 

performed,there must also be a driving force for it to 

occur (see above). Linking and unlinking operations are 

purely kinetic parameters and so can be accomplished by 

simply changing the rate of reactions rather than introducing 

or removing physical barriers. 

The statistical balance of a dynamic substrate and whether 

the parts of the machine acting on the substrate allow 

exchange of the substrate or not appear to be key factors that 

determine whether the machine can perform a useful task or 

not. In fact,it appears that the behavior of a molecular 

machine towards a substrate can be defined by the changing 

relationship (linked/unlinked,balanced/unbalanced) between 

the parts of machine interacting with the substrate. 

We can see that there are three fundamental types of 

Brownian machine that act through various combinations of 



balance-breaking,linking/unlinking,ratcheting,and escapement 

steps: Brownian switches (for example,the switchable 

molecular shuttles in Section 4.3),Brownian flip-flops (for 

example,rotaxane 85),and Brownian motors (for example,17 

or 46,see Sections 2.1.2 and 2.2). By combining these simple 

Brownian machine types with other combinational and/or 

sequential operations based on Boolean logic,machines of 

increasing complexity can be envisaged (Figure 28). 

1) A “Two-state (or multistate) Brownian switch” [32] is a 

machine that can reversibly change the distribution or 

position of a Brownian substrate between two (or more) 

distinguishable sites as a function of the state of the 

machine. It does this by biasing the Brownian motion of 

the substrate (Figure 26 a). Classic stimuli-responsive 

Figure 26. Schematic representations of some simple compartmentalized 

molecular-level machines. a) Two-state Brownian switch. b) Irreversible 

Brownian switch. c) A two-state Brownian flip-flop (shown 

operating through a partial energy ratchet mechanism; other mechanisms 

can achieve the same machine function). [32] 

molecular shuttles,such as those discussed in Section 4.3, 

are examples of two-state (or three-state,Section 4.3.9) 

Brownian switches. An “irreversible Brownian switch” is a 

“once only” machine,such as succ1-84 (Scheme 48),which 

irreversibly changes the distribution or position of a 

Brownian substrate in response to an external stimulus 

(Figure 26 b). 

2) A “Two-state (or multistate) Brownian flip-flop” [32] is a 

machine that can reversibly change the distribution or 

position of a Brownian substrate between two (or more) 

distinguishable sites and can be reset without restoring the 

original distribution of the substrate (Figure 26c). The 

statistical distribution of the substrate cannot be determined 

from the state of the flip-flop but rather is 

determined by the history of operation of the machine. 

Rotaxane 85 is an example of a two-state Brownian flipflop. 

3) A “Brownian motor” [32,255] is a machine that can repetitively 

and progressively change the distribution or position 

of a Brownian substrate,during which the machine is reset 

without restoring the original distribution or position of 

the substrate (Figure 27). Like a flip-flop,a Brownian 

motor affects a system as a function of the pathway that 

the machine takes,not as a function of state. [6] Indeed, 

Figure 27. Schematic representations of two types of Brownian 

motors: a) a two-stroke rotary motor and b) a three-compartment 

translational motor or pump. [32] 


Chemie 

even at the machine s steady state it can produce a net flux 

of a substrate in a given direction. The rotary motors 

designed by Feringa and co-workers (see Section 2.2) are 

examples of this category of machines. A catenane-based 

two-stroke rotary Brownian motor in which the substrate 

is repetitively transported between two sites through two 

alternating pathways is given in Section 4.6.3. 

4) In addition to switches,flip-flops,and motors,other 

machines can be envisaged that exploit selective,controlled 

manipulation of Brownian moieties (parts of the 

machine molecule or a substrate) far from equilibrium. By 

combining balance-breaking and linking/unlinking steps 

with Boolean logic functions,machines that can move a 

substrate (or itself) in different directions (Figure 28a) or 

sort and separate different ions (Figure 28b) can be 

invented. We have little doubt that many other types of 

machines that exploit and control non-equilibrium distributions 

of conformations and co-conformations will be 

designed and realized in the future. 

The requirements for linking and unlinking,for example, 

can also be achieved by using a substrate that has two or more 

sites that can interact with the track. In its simplest form,this 

requires a “walker” with at least two “feet” (similar to 

biological molecular motors such as kinesin) and directional 

motion along the track can then occur by several different 

categories of energy ratchet-based mechanisms,for example, 


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Reviews 

Figure 28. Schematic representations of some compartmentalized 

molecular-level machines that combine ratcheting and escapement 

with Boolean logic operations: a) a four-compartment Brownian 

machine that pumps a substrate in a given (variable) direction. 

Deciding which one of the purple or yellow gates is used for ratcheting 

determines whether the substrate is transported to the top compartment 

or the bottom. b) A four-compartment Brownian machine that 

sorts and separates different ions (for example, red = Na + , blue = K + ). 

A logic operation providing selective access through each of the purple 

and yellow gates ensures one type of ion is pumped into each 

compartment. [32] 

“passing-leg” (Figure 29 a) and “inchworm” (Figure 29 b). 

Using the ideas outlined above (and in Section 1.4.3) it 

appears to us that each of these mechanisms can be realized 

through several different permutations of binding sites on the 

track (which may be active or passive) and on the walker 

“feet” (which may also be active or passive),but the key 

elements of the mechanism are the same. Compartmentalization 

is achieved by having,at all times,at least one foot 

kinetically associated with a particular site on the track,while 

a free foot seeks out the most preferable binding site for itself 

by Brownian motion. Directionality is achieved by the 

relative arrangement of stations in the region of space that 

the free foot can explore—controlled by the mode of walking 

(stepping or inchworm) and the length of linker between the 

feet (which could also be varied in some mechanisms). In 

Section 4.6.2 we will see that an inchworm-type mechanism 

around a cyclic track can be achieved in a [3]catenane where 

the two “walking” rings are not joined,although it would not 

be possible to extend this to a repetitive linear track without 

connecting them together. Such systems which operate solely 

through changes in the walker itself may be regarded as “selfpropelled” 

walkers (see Section 6.2). 

Just like compartmentalized molecular machines in which 

linking/unlinking is controlled by changes in the track 

(Figures 26–28),one can also envisage walkers which incorporate 

more complex functions,such as Boolean logic 

operations to select between a choice of pathways (Figure 

29c). Furthermore,an information ratchet mechanism 

may also be used to control the directionality of a walker,for 


Figure 29. Schematic representations of compartmentalized molecular 

machines which use attachment of the substrate to a track to prevent 

a Brownian substrate from adopting a statistical thermodynamic 

equilibrium distribution. a) A “passing-leg” walker is ratcheted by 

fixing the “front” foot to the track while the rearmost foot swings 

forward to bind at a site further down the track in the direction of 

travel. b) In an “inchworm” walker, the order of the feet is prevented 

from changing (for example, by using rings to mechanically link to the 

track as illustrated here) and ratcheting occurs by first fixing the rear 

foot to the track while the front moves, then fixing this foot in place 

while the rear one moves. c) These mechanisms can be combined with 

more complex functions such as Boolean logic operations to allow a 

passing-leg walker to choose between different pathways. d) Information 

ratchet mechanisms can also be employed by walker compartmentalized 

machines, such as a “burnt-bridges” walker which destroys 

the track to the rear whenever a step is taken in the intended direction 

of travel. 

example a walker that irreversibly destroys its track when 

making a step in one direction,but not the other (Figure 29 d). 

4.5. Controlling Rotational Motion in Rotaxanes 

Macrocycle pirouetting in rotaxanes presents two challenges 

in terms of control: the frequency of the random 

motion and its directionality. The former can be achieved 

through temperature,structure,electric fields,light,and 

solvent effects; the latter has yet to be demonstrated. [256] 

Alternating current (a.c.) electric fields represent an ideal 

stimulus with which to control submolecular dynamics in 

many applications. In the two [2]rotaxanes 86 and (E)-87 

(Scheme 50),it was observed that application of a.c. fields of 

around 50 Hz resulted in unusual Kerr effect responses which 

are unique to the interlocked architecture (they are not 

observed for either of the components alone). [257] Increasing 



Scheme 50. [2]Rotaxanes 86 and 87 in which the rate of pirouetting 

can be controlled by application of an alternating current electric 

field. [257] 

the temperature had the same effect as decreasing the field 

strength,namely,enhancement of the response. The same sort 

of Kerr effects have previously been seen with rigid-rod 

polymers and correlated with the dynamics of the polymer 

backbones. [258] Variable temperature (VT) 1 H NMR experiments 

and molecular-modeling studies confirmed that macrocycle 

pirouetting is the only dynamic process in the rotaxanes 

on this timescale. The experimental and theoretical studies 

also predict the slightly more complex Kerr effect response 

observed experimentally for 87 relative to that of 86. It was 

concluded that application of an a.c. electric field 

attenuates macrocycle pirouetting in 86 and 87, 

probably by polarizing and strengthening intercomponent 

hydrogen bonding. The extent of the 

dampening can be varied with the strength of the 

applied field; even modest fields of about 1 V cm 1 

produce pirouetting rate reductions of two to three 

orders of magnitude. 

An alternative strategy for affecting pirouetting 

rates is to apply a stimulus which directly 

alters the structure of the thread or macrocycle. 

This has been demonstrated to great effect for 

olefin-containing [2]rotaxanes (E)/(Z)-87–89 

(Scheme 51). [259] The decrease in intercomponent 

binding affinity on photoisomerization of the 

fumaramide units in (E)-87–89 to the cis-maleamide 

isomers gives a huge increase in the rate of 

pirouetting of more than six orders of magnitude. 

The switching process is reversible: subjecting the 

maleamide rotaxanes to heat or a suitable catalyst results in 

reisomerization to the more thermally stable trans-olefin 

isomers,with accompanying reinstatement of the strong 

hydrogen-bonding network. 

Binding of sodium or potassium cations to a crown ether 

embedded in a rotaxane macrocycle has been shown experimentally 

to retard co-conformational Brownian motion, 

particularly pirouetting. [260] Removal of the metal template 

from a rotaxane can induce rotation of the ring relative to the 

thread, [261] while incorporating two different coordination 

sites into a macrocycle can be used to control the rotational 

orientation of components in a manner analogous to the 

translational shuttling modes discussed in Section 4.3.4. [262] 

This pirouetting motion,however,tends to be faster than the 

Scheme 51. Photoisomerization of [2]rotaxanes (E)-87–89 which results 

in pirouetting rate enhancements of up to six orders of magnitude. [259] 

The reverse process (Z!E isomerization) can be effected by heating a 

0.02m solution of the Z rotaxanes at 400 K, generating bromine 

radicals (cat. Br 2, hn 400 nm), or through reversible Michael addition 

of piperidine (RT, 1 h). 

analogous shuttling modes and in the particular example 

illustrated in Scheme 52 for [Cu(90)],the pirouetting rate is 

further enhanced by using an unhindered bipyridine ligand in 

the thread,from which the bulky stoppers are well separated. 

[262e] 

Scheme 52. Electrochemically triggered rapid pirouetting motion in metal-templated 

[2]rotaxane [Cu(90)]. [262e] 

4.6. Controlling Rotational Motion in Catenanes 

4.6.1. Two-Way and Three-Way Catenane Positional Switches 


Chemie 

As with rotaxanes,stimuli-induced structural changes can 

be used to alter the rates of the thermal intercomponent 

motions in catenanes. For example,photoisomerization of an 

azobenzene unit in a p-donor/acceptor [2]catenane was found 

to influence the rate of dynamic processes,presumably by 

altering the size of the macrocycle cavity. [263] Electrochemical 

reduction of a homocircuit benzylic amide [2]catenane 

completely halts the circumrotational process as a result of 

the formation of an intercomponent covalent bond between 

the macrocycles. [264] Protonation of a porphyrin free base in a 

catenane was found to result in a rearrangement to minimize 


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repulsive electrostatic interactions,thus altering the rate of 

pirouetting of a tetracationic cyclophane. [191w,265] Electrochemical 

studies suggest similar conformational and dynamic 

changes can occur on reduction of the cyclophane. [266] 

The fundamental principles for controlling the position of 

a macrocycle on a thread in a rotaxane and the relative 

positions and orientations of the rings in a catenane are the 

same. For example,the behavior of amphiphilic homocircuit 

[2]catenane 91 is governed by the same driving forces that 

cause solvent-induced shuttling in amphiphilic shuttle 58 (see 

Sections 4.2.1 and 4.3.10). [267] In halogenated solvents such as 

CDCl 3,the two macrocycles of 91 interact through hydrogen 

bonds (amido-91,Scheme 53,also the structure observed in 

Scheme 53. Translational isomerism in an amphiphilic benzylic amide [2]catenane 91. [267] 

the solid state) whereby each constitutionally identical ring 

adopts a different conformation,one effectively acting as the 

host (convergent H-bonding sites) and the other the guest 

(divergent H-bonding sites). Pirouetting of the two rings 

interconverts the host–guest relationship rapidly on the NMR 

timescale in CDCl 3 at RT. In a hydrogen-bond-disrupting 

solvent such as [D6]DMSO,however,the preferred coconformation 

has the amide groups exposed on the surface 

where they can interact with the surrounding medium,while 

the hydrophobic alkyl chains are buried in the middle of the 

molecule to avoid disrupting the structure of the polar solvent 

(alkyl-91,Scheme 53). [268] 

In heterocircuit [2]catenanes such as 92 4+ the change in 

the position of one macrocycle with respect to the other is 

even more reminiscent of shuttling in [2]rotaxanes (Scheme 

54). [184l,228a] In the ground state (92 4+ ) the tetracationic cyclophane 

(blue) mostly sits over the more electron rich TTF 

station (green). Oxidation of the TTF (green!pink) to either 

its radical cation or dication (92 5+ or 92 6+ ) can be achieved 

chemically or electrochemically and results 

in the cyclophane being positioned over the 

dihydroxynaphthalene unit (DNP,red). The 

movement can be reversed by reduction of 

the TTF unit back to its neutral state. Just as 

for the rotaxane derivatives in this series 

(Section 4.3.4),[2]catenane 92 4+ exhibits 

rapid shuttling away from the TTF station 

and slower kinetics for the return 

step. [228f,269] There is,of course,no control 

over the direction in which the motion 

occurs; the cyclophane has a choice of two 

routes between the stations in both directions 

and half the molecules will change 

position in one direction and the other half in the other. [270,271] 

Electrochemical co-conformational switching has also 

been observed for [2]catenane 93,which features a crown 

ether threaded onto a large macrocycle containing two cyclen 

rings containing different metal ions (Scheme 55). [272] In both 

the solution and solid states,the crown ether sits over the 

Scheme 54. Chemically and/or electrochemically driven translational isomer switching of [2]catenane 92 4+ to 92 5+ /92 6+ [184l, 228a] 

. 

Scheme 55. Electrochemically induced co-conformational changes in a heterodinuclear [2]catenane. [272] 




Ni II center. However,the Cu II ion is more easily oxidized than 

Ni II ion,and the resulting Cu III center provides an effective 

electron-poor station for the p-donor macrocycle. Subsequent 

oxidation of the nickel ion moves the crown ether back to its 

original site. 

In the classical metal-templated [2]catenates pioneered by 

the Sauvage group (for example,[Cu I (94)],Scheme 56), [273] 

Scheme 56. The original metal-templated [2]catenate, [Cu I (94)]. [273] 

Removal of the Cu I ion results in reorganization of the organic ligands 

to present the diphenylphenanthroline units (light blue) on the outer 

surface. [274] The resultant [2]catenand free ligand can complex a wide 

range of metal ions. [275,276] 

removal of the metal template to give the corresponding 

[2]catenand often results in significant co-conformational 

changes. In nonpolar solvents and the solid state,the 

polyether chains are buried in the center of the molecule, 

Scheme 57. Reversible co-conformational switching in a hybrid coordination/charge transfer [2]catenane. [277] 


Chemie 

thus presenting the heterocyclic ligands to the outside. [274] The 

process is often fully reversible—indeed,complexation of a 

variety of cations can be achieved with the [2]catenand 

(including Li + ,Fe 2+ ,Co 2+ ,Ni 2+ ,Cu + ,Zn 2+ ,Ag + ,Cd 2+ ,and 

even H + ),in each case restoring the original complexed coconformation 

shown in Scheme 56. [275,276] 

Introducing a second,orthogonal,set of possible interactions 

between the two rings can make the co-conformational 

changes better defined. The presence of p-electrondonor 

(red) and p-electron-acceptor (dark blue) units on the 

two macrocycles in [2]catenate [Cu I (95)] 5+ (Scheme 57) [277] 

means that a precisely defined co-conformation ensues on 

demetalation to give [2]catenand 95 4+ ,which is stabilized by 

p–p charge-transfer interactions. A similar switching process 

can also be achieved reversibly simply by protonation and 

deprotonation (Scheme 57). Anion binding has been shown 

to result in an alteration of the co-conformational arrangement 

of a bipyrrole-based [2]catenane templated by hydrogen-bonding 

interactions. [278] 

In a series of [2]catenates formed around square-planar 

templates,demetalation does not result in a significant coconformational 

change. [279] [2]Catenane 96 was generated in 

this fashion,but it was then found that the templating metal 

(Pd II ) can either be reinserted along with concomitant 

deprotonation of two amide nitrogen atoms to give the 

original catenate or else complexation to only one ring can be 

achieved,thereby producing a half-turn in the relative 

orientation of the components. [280] All three forms are fully 

interconvertible (Scheme 58) and can be observed in both 

solution and the solid state. 

Steps towards photochemical switching in metal-templated 

catenates have also recently been taken,by making use 

of the ready access of dissociative d-d* excited states in 

ruthenium(II) complexes with distorted octahedral geome- 


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Reviews 

Scheme 58. Half-rotation in a [2]catenane through interconvertible Pd II coordination modes. [280] 

tries. [281] Irradiation (l > 300 nm) of [2]catenate 97 results in 

dissociation of the bipyridyl unit (red),which allows free 

movement of the two rings (Scheme 59). The vacant coordination 

sites on the metal ion are filled by chloride ions added 

to the reaction mixture (shown) or by a coordinating solvent 

such as acetonitrile (not shown). [282] The recomplexation 

reaction is achieved simply by heating. [283] 

Sauvage and co-workers have also demonstrated both 

electrochemical and photochemical control over ring motions 

in hetero-[2]catenate 98 (Scheme 60 a) which is closely related 

to molecular shuttle 74 (see Section 4.3.4). [284] The behavior 

observed for the catenate is essentially the same as its 

rotaxane analogue. The kinetics for the intercomponent 

motions are again slow relative to other molecular machines, 

although some differences are observed between the catenane 

and rotaxane on account of easier access of the solvent 


or ionic species to the metal center 

in the rotaxane,thus stabilizing 

transition states on the way to 

species with higher coordination 

numbers. 

The related homocircuit [2]catenate 

[Cu(99)] (Scheme 60b),in 

which each ring contains a bidentate 

dpp unit and tridentate terpy site, 

exhibits more complicated behavior. 

[285] 

In dpp,dpp-[Cu I (99)],the 

copper ion coordinates to the two 

dpp units in the usual tetrahedral 

arrangement. Oxidation of the 

metal center (by either chemical or 

electrochemical means) reverses the 

order of preference for coordination 

numbers (the preferred order for 

Cu II is 6 > 5 > 4). The result is circumvolution 

of the rings to give the 

preferred hexacoordinated species 

terpy,terpy-[Cu II (99)]. It was demonstrated 

that this process occurs by 

revolution of one ring to give an 

intermediate five-coordinate species 

(dpp,terpy-[Cu II (99)]). [285] 

In 

comparison to many related transition-metal-coordinated 

systems,the process is relatively fast,with the ligand 

rearrangement occurring on the timescale of tens of seconds. 

The process is completely reversible,via the same fivecoordinate 

geometry,on reduction to Cu I (that is,via 

dpp,terpy-[Cu I (99)]). 

Accordingly,this catenate adopts three different translational 

isomeric forms (six different states when the oxidation 

state of the metal ion is considered). The intermediate fivecoordinate 

states are only transient,however,and could not 

be isolated. A system which displays three distinct,stable 

states is [2]catenane 100 (Scheme 61). This catenane,and the 

related [3]catenane 101,extend the olefin photoisomerization 

strategy utilized in [2]rotaxanes 80, 83,and 87–89 to create the 

first examples of stimuli-driven sequential and unidirectional 

rotation in interlocked molecules,thereby addressing the key 

Scheme 59. Photoinduced selective decomplexation in a ruthenium(II) [2]catenate. [282] In the decomplexed form [97 2+ ·2 Cl ], no bonding 

interactions exist between the two rings and free rotation occurs. The co-conformation shown is purely illustrative and does not indicate a 

preferred arrangement. 



Scheme 60. a) Heterocircuit switchable catenate [Cu(98)]. [284] b) Oxidation-state-controlled switching of [2]catenate [Cu(99)] between three distinct 

co-conformations. [285] 

Scheme 61. [2]Catenane 100 and [3]catenane 101, shown as their 

E,E isomers. [286] 

difference between shuttling in two-station rotaxanes and 

rotation in catenanes (closely related to the difference 

between a switch and a motor,see Section 1.1): the issue of 

directionality. [286] 

Sequential movement of one macrocycle between three 

stations on a second ring requires independent switching of 

the affinities for two of the units so as to change the relative 

order of binding affinities,as shown schematically in 

Figure 30. [286] In 100 this is achieved (Scheme 61) by employing 

two fumaramide stations with differing macrocycle binding 

affinities (steric mismatching of some tertiary amide 

rotamers disfavor the methylated station B),one of which 

(station A,green) is located next to a benzophenone unit. 

This allows selective photosensitized isomerization of station 

A at 350 nm,before photoisomerization of the other 

fumaramide station (station B,red) at 254 nm. The third 

station (station C,orange),a succinic amide ester,is not 

photoactive and is intermediate in macrocycle binding affinity 

Figure 30. Stimuli-induced sequential movement of a macrocycle 

between three different binding sites in a [2]catenane. [286] 


Chemie 


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Reviews 

between the two fumaramide stations and their maleamide 

counterparts. A fourth station,an isolated amide group 

(shown as D in (E,E)-101) which can make fewer intercomponent 

hydrogen bonding contacts than A,B,or C,is also 

present but only plays a significant role in the behavior of the 

[3]catenane. 

Consequently,in the initial state (state I,Figure 30),the 

small macrocycle resides on the green,nonmethylated 

fumaramide station of [2]catenane 100. Isomerization of this 

station (irradiation at 350 nm,green!blue) puts the system 

out of co-conformational equilibrium and the macrocycle 

changes its net position to the new energy minimum on the 

red station (state II). Subsequent photoisomerization of this 

station (irradiation at 254 nm,red!purple) displaces the 

macrocycle to the succinic amide ester unit (orange,state III). 

Finally,heating the catenane (or treating it with photogenerated 

bromine radicals or piperidine) results in isomerization 

of both the Z olefins back to their E forms (purple! 

red and blue!green) so that the original order of binding 

affinities is restored and the macrocycle returns to its original 

position on the green station (state I). 

The 1 H NMR spectra of each diastereomer show excellent 

positional integrity of the small macrocycle at all stages of the 

process,but the rotation is not directional—over the complete 

sequence of reactions,an equal number of macrocycles go 

from A,through B and C,back to A again in each direction. 

4.6.2. Directional Circumrotation: A [3]Catenane Rotary Motor 

To bias the direction the macrocycle takes from station to 

station in a catenane such as 100,kinetic barriers are required 

to restrict Brownian motion in one direction at each stage and 

bias the path taken by the macrocycle. Such a situation is 

intrinsically present in [3]catenane 101 (Scheme 61). [286] 

Irradiation of (E,E)-101 at 350 nm causes counterclockwise 

(as drawn) rotation of the light blue macrocycle to the 

succinic amide ester (orange) station to give (Z,E)-101. 

Isomerization (254 nm) of the remaining fumaramide group 

causes the other (purple) macrocycle to relocate to the single 

amide (dark green) station ((Z,Z)-101) and,again,this occurs 

counterclockwise because the clockwise route is blocked by 

the other (light blue) macrocycle. This “follow-the-leader” 

process,in which each macrocycle in turn moves and then 

blocks a direction of passage for the other macrocycle,is 

repeated throughout the sequence of transformations shown 

in Figure 31. After three diastereomer interconversions, 

(E,E)-101 is again formed,but 3608 rotation of each of the 

small rings has not yet occurred,they have only swapped 

places. Complete unidirectional rotation of both small rings 

occurs only after the synthetic sequence (a)–(c) has been 

completed twice. 

The directionality of the movement of the small macrocycles 

in Figure 31 could only be inferred from dynamic 

studies on related rotaxane-based molecular shuttles. [286] 

Nevertheless,these imply that stimuli-induced rotation carried 

out at 195 K occurs with extremely high (> 99%) 

directional fidelity. The DG ° value for background rotation 

of the small rings in (E,E)-101 is greater than 23 kcalmol 1 , 

which means that the half-life for random circumrotation at 


Figure 31. Stimuli-induced unidirectional rotation in a four-station 

[3]catenane, 101. [286] Conditions: a) irradiation at 350 nm; b) irradiation 

at 254 nm; and c) D; or catalytic ethylenediamine, D; or catalytic Br 2, 

irradiation at 400–670 nm. 

195 K is over 1.5 years. This design could only be used to do a 

limited amount of progressive mechanical work since the only 

way that the ring movements are ratcheted is the relatively 

modest DG ° value for background rotation. The efficiency of 

this motor is either poor (< 1 % based on irradiated photons) 

or modest (ca. 17 %,based on molecules that unidirectionally 

rotate during one sequence of reactions). Unlike the directionally 

rotating systems introduced by the research groups of 

Kelly (Section 2.1.2) and Feringa (Sections 2.1.2 and 2.2), 

[3]catenane 101 is achiral. 

It seems likely that the designs (and modes of operation) 

of synthetic molecular machines will provide significant 

feedback for the understanding and development of new 

fluctuation-driven transport mechanisms. If we compare 

[2]catenane 100 with [3]catenane 101,for example,we can 

see that they share a common track or potential-energy 

surface that is manipulated by the same set of chemical 

reactions. However,in [3]catenane 101 the Brownian particle 

(macrocycle) is transported directionally while in [2]catenane 

100 it is not. The only difference between the two machines is 

the “concentration” of the Brownian particles on the 

potential-energy surface. It seems possible that such a 

mechanism could account for the dependence of some 

biological pumps on the substrate concentration. 

4.6.3. Selective Rotation in Either Direction: A [2]Catenane 

Reversible Rotary Motor 

Clearly,just like their rotaxane analogues,catenanes such 

as 101 can be viewed as one macrocycle (the machine) which 



provides a potential-energy surface over which one (or more) 

smaller ring(s) (the Brownian substrate(s)) can be transported. 

By considering a flashing ratchet mechanism (Section 

1.4.2),it is possible to design a [2]catenane which is able 

to directionally rotate the smaller ring about the larger one in 

either direction in response to a series of chemical reactions 

(shown schematically in Figure 32). [51,287] 

This concept was realized in chemical terms through the 

synthesis and operation of catenane fum-(E)-102 

(Scheme 62). [51] Net changes in the position or potential 

energy of the smaller ring were sequentially achieved by: 

a) photoisomerization to maleamide (!mal-(Z)-102); 

b) desilylation/resilylation (!succ-(Z)-102); c) reisomerization 

to fumaramide (!succ-(E)-102); and finally,d) detritylation/retritylation 

to regenerate fum-(E)-102,the whole 

reaction sequence producing a net clockwise (as drawn in 

Scheme 62) circumrotation of the small ring about the larger 

one. Exchanging the order of steps (b) and (d) produced an 

equivalent counterclockwise rotation of the small ring. 

The simplicity of 102,together with the minimalist nature 

of its design,allows insight into the fundamental role each 

part of the structure plays in the operation of the rotary 

machine. [2]Catenane 102 is easily understood as an example 

of a compartmentalized molecular machine (see Section 4.4). 

The various chemical transformations perform linking/ 

unlinking reactions (silylation/desilylation 

and tritylation/detritylation) 

and balance-breaking reactions 

(olefin isomerization (E!Z and 

Z!E)). As with other compartmentalized 

molecular machines,the balance-breaking 

reactions control the 

thermodynamics and impetus for net 

transport; the linking/unlinking reactions 

control the relative kinetics and 

ability to exchange. Raising the 

kinetic barriers ratchets transportation 

(see Section 4.4),thus allowing 

the statistical balance of the small ring 

to be subsequently broken without 

reversing the preceding net transportation 

sequence. Lowering the kinetic 

barrier allows escapement (see Section 

4.4) of a ratcheted quantity of 

rings in a particular direction—the 

element missing from rotaxane 85, 

which prevents it being a molecular 

motor. 

To obtain 3608 rotation of the 

small ring about the large ring,the 

four sets of reactions must be applied 

in one of two sequences,each taking 

the form: first a balance-breaking 

reaction; then a linking/unlinking 

step; then the second balance-breaking 

reaction; and finally,the second 

linking/unlinking step. This is the 

same manipulation of the potentialenergy 

surface shown for the flashing 

Figure 32. a) Schematic illustration and b) potential-energy surface for 

the blue ring in a minimalist [2]catenane rotary molecular motor. [51] 

Scheme 62. Reversible [2]catenane rotary motor 102. [51] 


Chemie 


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Reviews 

ratchet in Figure 7 (Section 1.4.2). The direction of net 

rotation is determined solely by the way the balance-breaking 

and linking/unlinking steps are paired: an input of information. 

The efficiency or yields of the reactions—or the position 

of the ring at any stage (even if the machine makes a 

“mistake”)—are immaterial to the direction in which net 

motion occurs,as long as the reactions continue to be applied 

in the same sequence. Changing the pairings rotates the small 

ring in the opposite direction. 

The analysis of this deceptively simple molecule,particularly 

the separation of the kinetic and thermodynamic 

requirements for detailed balance,provides experimental 

insight into how an energy input is essential for directional 

rotation of a submolecular fragment by Brownian motion. 

Even though no net energy is used to power the motion,there 

has to be some processing of chemical energy for net rotation 

to be directional over a statistically significant number of 

molecules,a requirement that is absent if the equivalent 

motion is nondirectional. The amount of energy conversion 

required to induce directionality has an intrinsic lower limit, 

which corresponds to the difference in the binding energy of 

the fumaramide and maleamide binding sites,the same value 

that determines the directional efficiency of rotation and the 

maximum amount of work the motor can theoretically 

perform in a single cycle. 

5. Molecular-Level Motion Driven by External Fields 

In most of the synthetic molecular machines described so 

far,control over motion arises from the selective restriction of 

Brownian fluctuations through the manipulation of chemical 

structure,composition,and electronics to influence steric and 

noncovalent bonding interactions. Common to all these 

approaches is that the forces exerted are short range—steric 

interactions are only felt over van der Waals distances,while 

bonding interactions (hydrogen bonds,charge-transfer interactions,or 

metal–ligand coordination) also operate over very 

short distances—and it is almost always thermal energy that 

powers the large-amplitude motions. It is well known that the 

application of external fields can cause bulk motion or 

orientation of molecular species,the most important technological 

application being the electric-field-directed alignment 

of liquid crystals. In addition to their more well-known 

applications,electrophoresis, [44l–n,q,v] dielectrophoresis, [44a,d,f,h,t] 

and photon pressure [44b,c] have been shown to provide 

potentials in which the motion of microscopic particles and 

macromolecules can be manipulated through Brownian 

ratchet mechanisms. An emerging field of research,however, 

aims to use the long-range forces that can be applied by 

external electric and electromagnetic fields to influence 

submolecular motions. The effect of alternating current 

electric fields on the rate of random pirouetting in rotaxanes, 

which has already been discussed (Section 4.5),is just one 

example. 

Electric-field-controlled conformational switches have 

been proposed to create switchable molecular junctions for 

use in molecular electronics. [288] Computational investigations 

of 103 chemisorbed between two electrodes (Scheme 63) 

Scheme 63. A proposed molecular rectifier based on field-driven conformational 

switching. [289] 

have suggested that an electric-field-induced conformational 

change (arising from interaction of the field with the dipolar 

rotator,red) could result in a significant change in the 

conductance of the tunnel junction,thus resulting in a 

“conformational molecular rectifier”. [289] From a molecular 

electronics perspective,in both single-molecule junctions and 

STM-contacted molecules (see Section 7),the ability of the 

electric current to induce dynamic motion of a molecule after 

transient electronic excitation is becoming a matter of both 

theoretical and practical investigation. [290] 

In terms of using long-range fields to drive the motions of 

a collection of molecular machines,the main challenge which 

has been addressed is the generation of submolecular rotary 

motion. [1k] The 3608 rotation of any rotor involves passage 

over a torsional potential-energy surface,with its particular 

series of minima and maxima. The effect of an external field 

could be to: 1) promote the system to an excited state where 

the torsional potential-energy surface is different,or 2) interact 

with a permanent,or induced,molecular dipole so as to 

force orientation in a particular direction. The interaction 

between the field and the rotor provides the energy to 

surmount kinetic barriers and overcome energy dissipation 

and thermal randomization,so the field strength may need to 

be relatively large. With these intended systems,random 

thermal noise and dissipative effects such as friction would 

need to be minimized to maximize efficiency (for the 

problems in doing so,see Section 1.2). However,the requirements 

for generating unidirectional motion are no different 

from those under the thermally driven regime: asymmetry in 

the potential-energy surface and an energy input which can 

drive the system away from equilibrium. 

This type of rotary device is likely to 

require orientation of the rotational axis 

along a fixed direction by using surfacemounted,solid-state,or 

liquid-crystal 

rotors. However,the consideration of 

small molecules in the gas phase as 

models has allowed high-level quantum 

dynamics simulations of such a process. 

Fujimura and co-workers have studied 

the internal rotation in the single enantiomeric 

forms of chiral aldehyde 104, 

driven by an intense linearly polarized 

infrared laser pulse on the picosecond 

timescale (Scheme 64). [291,292] The chiral- 


Scheme 64. One enantiomer 

of chiral 

molecule 104 in 

which electric-fielddriven 

rotation 

around the C CHO 

bond was studied by 

quantum and classical 

mechanical sim- 

[291,293, 295,326] 

ulations. 



ity of 104 means that it has an asymmetric potential-energy 

surface for rotation about the C CHO bond,while energy 

sufficient to surmount the highest potential-energy barrier is 

provided by interaction between the electric field of the laser 

pulse and the permanent dipole of the aldehyde. The process 

is reminiscent of a rocking Brownian ratchet (Section 1.4.2.2), 

although here thermal energy is not required to surmount the 

kinetic barriers. The system can also be modeled as an 

ensemble of randomly oriented rotors,but in either case the 

result is unidirectional motion and the two enantiomers rotate 

with equal magnitudes but in opposite directions (within the 

molecular frame of reference). 

In the above calculations dissipative effects were ignored. 

Inertia therefore plays a significant role and rotation is seen to 

continue even after the driving field is removed. As discussed 

in Section 1.2.2,it is somewhat debatable how applicable such 

conditions are to practical situations in which molecular 

machines might operate. Fujimura and co-workers have 

subsequently taken energy dissipation into account,and 

have shown that,as one might expect,rotation only occurs 

under these conditions while the field is applied. [293] It was 

also found that on reducing the field intensity so that the 

field–dipole interaction falls below the maximum kineticbarrier 

height,rotation occurs in the opposite direction,with 

barrier crossings mediated by quantum effects. Such behavior 

bears a striking resemblance to rocked quantum-tunneling 

ratchets designed to pump electrons. In such cases,the 

direction of electron transport has been shown (both experimentally 

and theoretically) to switch with rising temperature, 

depending on whether quantum tunneling though the kinetic 

barriers (low temperatures) or thermally activated barrier 

crossing (high temperatures) is the dominant process. [294] The 

quantum control of rotational direction in enantiomerically 

pure 104 was further elucidated by studies in which the timeand 

frequency-resolved spectra of the laser electric field were 

examined and the conditions for generating rotation in each 

direction were optimized. [295] 

A number of computational studies of idealized graphite 

nanotube dynamics have been undertaken [296] in structures 

reminiscent of some of the futuristic “hard” nanotechnology 

machine components envisioned by Drexler. [297] The interactions 

between concentric nanotubes (that is,in doublewalled 

nanotubes (DWNTs) and multiwalled nanotubes 

(MWNTs)) have received considerable attention with 

regard to their predicted low friction for relative sliding and 

rotational motions. [298] So-called “molecular bearings” in 

which the inner tube can be rotated within an outer sleeve 

have been studied, [299] as have “nanodrills” in which the 

interaction between the tubes is such that a rotational torque 

on one tube is converted into translation relative to the 

other. [300] Also proposed is the possibility of a gear effect for 

two parallel single-walled nanotubes (SWNTs) functionalized 

with benzyne-derived “teeth” along their length. [301] Potential 

methods for powering motions in all these systems clearly 

need to be considered. Attaching opposite charges to the 

inner tube of a DWNT molecular bearing in a molecular 

dynamics study enabled the coupling of the energy from a 

linearly polarized laser field with rotational modes of the 

system to be simulated. [302] A similar approach was used to 

study the theoretical motion of a SWNT gear system. [303] 

When the simulated gearing effect was used to transmit 

angular momentum to a noncharged nanotube,periods of 

induced directional rotation grew longer. [304] A further class of 

proposed nanotube-based mechanical devices are oscillators, 

in which the inner tube should be able to shuttle back and 

forth inside an open-ended outer tube at gigahertz frequencies. 

[305] Again the problems of powering the proposed 

motions and providing environments in which they could be 

effective must be tackled. One scenario has been modeled in 

which the inner tube encapsulates potassium ions and its 

oscillatory motion is driven by an external electric field, [306] 

while another has proposed thermal expansion of gases to 

power the motion. [307] However,the arrival of the experimental 

techniques required to produce or operate any of 

these systems in practice appears to be distant. The chemical 

functionalization of nanotubes is,however,a rapidly developing 

field, [308] while improved manipulation techniques have 

allowed the telescoping of inner tubes from a MWNT,and 

have demonstrated extremely low friction and a large driving 

force for the retraction of the extended structure. [309,310] 

Rotors driven by circularly or linearly polarized electric 

fields [311] have been investigated by Michl and co-workers. 

Their approach closely follows an experimental effort to 

create surface-mounted dipolar rotors and so their calculations 

had to tackle technologically relevant conditions and 

complex structures. Dipolar chiral rhenium complex rotor 

105,was attached to a molecular grid constructed from 

[2]staffanedicarboxylate edges and dirhodium tetracarboxylate 

vertices (Scheme 65). [312,313] The theoretical rotational 

Scheme 65. Chiral dipolar rotor 105 which was studied computationally 

mounted on a 2D supramolecular framework and driven by a 

rotating electric field. [312] 


Chemie 

motion,driven by a circularly polarized electric field in a 

vacuum and at low temperature,was studied by molecular 

dynamics over a range of field frequencies and field strengths. 

At low field frequencies,the simulations suggest that the 

average lag angle (the position of the rotator in the rotating 

field coordinate system) depends only on the field strength,as 

the major restriction to unidirectional rotation is thermal 

energy. At higher frequencies,friction is the dominant 

hindrance to directional motion and appears to be linearly 

proportional to the driving frequency. Five different rota- 


129

Reviews 

tional regimes were characterized,depending on the interplay 

of the field–dipole interaction,thermal energy,friction,and 

intrinsic torsional barrier height. These range from synchronous 

motion,where the rotator slavishly follows the field,to 

situations where thermal energy or the torsional barrier 

dominates the behavior. [312,314] 

Michl and co-workers have synthesized nonpolar and 

dipolar altitudinal rotors (that is,rotors with axles parallel to 

the surface) 106 and 107 (Scheme 66). [315] 19 F NMR spectroscopy 

showed that the barriers to rotation in 107 were 

extremely low in solution. Both systems have also been 

adsorbed on Au(111) and the surfaces studied by X-ray 

photoelectron spectroscopy (XPS),scanning tunneling 

microscopy (STM),and grazing incidence IR spectroscopy. 

It was found that,for a fraction of the molecules,the static 

electric field from the STM tip could induce an orientational 

change in the dipolar rotor but not the nonpolar analogue. [316] 

The propeller-like conformation of the tetraarylcyclobutadienes 

means that 107 can exist as three pairs (residual 

diastereomers) of helical enantiomers. Approximate molecular 

dynamics simulations have predicted an asymmetric 

rotational potential energy surface for at least one out of the 

three diastereomers,so that unidirectional rotation can be 

predicted for this isomer on application of an alternating 

current electric field. [317,318] The Michl research group has also 

reported initial synthetic investigations of an alternative,selfassembled,altitudinal 

rotor design,although no functional 

studies have yet been reported. [319] Jian and Tour have 

reported the synthesis of dipolar rotors such as 108 and 

their monolayer formation on gold (Scheme 67),but have yet 

to communicate any results on its field-driven motion. [320] 

The above examples all consist of either permanent 

molecular dipole moments within a chiral structure,driven by 

achiral fields or else by a chiral field and therefore not 

requiring a chiral structure. Permanent molecular dipoles are 

not necessarily required however. If the rotator has a strongly 

anisotropic molecular polarizability,a dipole can be induced 

and rotated by an applied circularly polarized field. This has 

been proposed, [321] and experimentally achieved, [322] by subjecting 

chlorine molecules to an intense linearly polarized 

laser pulse,the polarization of which is rotating. In this 

“optical centrifuge” extremely high rotational energy levels 

can be accessed in very short time periods and the centrifugal 

force can induce bond dissociation. 


Scheme 67. Dipolar rotor 108 designed to be attached to gold 

surfaces. [320] 

An approach which has yet to be investigated experimentally 

[323] 

is the transfer of momentum from a directional 

stream of atoms or molecules to bias the rotation of 

components of molecules fixed to a surface. Three possible 

arrangements can be envisaged: [1k] 1) fluid flow parallel to the 

rotor axle,combined with a chiral propeller-like rotator 

(windmill-like operation); 2) fluid flow perpendicular to the 

rotor axle,with faster flow on one side of the axis of rotation 

than the other (waterwheel-like operation); and 3) fluid flow 

perpendicular to the rotor axle,combined with rotator blades 

which interact with the fluid particles differently on either 

side (operating somewhat like an anemometer). Vacek and 

Michl have modeled the second of these possibilities for chiral 

rotor 105 (Scheme 65) as well as an analogue bearing larger 

blades. [324] The molecular dynamics simulations,in which a 

supersonic jet of noble gas atoms was directed parallel to the 

rotor axis through the open grid structure on which it was 

mounted,suggested that high-density beams of lighter atoms 

(He or Ne,but not Ar or Xe) might indeed be able to induce 

Scheme 66. Nonpolar (106) and dipolar (107) altitudinal rotors which have been studied on Au(111) surfaces. Note that the rotator and flanking 

aryl rings are arbitrarily shown perpendicular to the surface for clarity. Interaction with the surface is through several atoms in the cyclopentadienyl 

“tentacle” substituents. [315,317] 



directional rotation,albeit at low temperatures and in 

competition with deformation of the rotor. [325] 

Fujimura and co-workers performed calculations that 

consider exploiting the different torsional potential-energy 

surfaces in the electronic ground and excited states of 104 

(Scheme 64) to achieve unidirectional rotation. [326] A femtosecond,UV-frequency 

pulse was used to excite the molecule 

to its first excited state. As a vertical transition does not 

correspond to a minimum in the excited-state potentialenergy 

surface,rotation is induced,the direction of which is 

governed by the gradient of the potential-energy surface in 

the Franck–Condon region (opposite in each enantiomer). In 

theory,if the molecules are returned to the electronic ground 

state by a second femtosecond pulse before the excited-state 

minimum is reached,then the angular momentum can be 

preserved and rotation continues in the same direction. Of 

course,Brownian thermal and frictional effects will very 

quickly degrade such motion and relaxation must next be 

taken into account to ascertain if sequential such “pump– 

dump” cycles would be able to maintain unidirectional 

rotation. A related approach was applied to theoretically 

consider rotation around the double bond in 109 

(Scheme 68). [327] In this case,an IR-frequency pulse would 

be used to excite vibrational motion in 

the deep torsional potential well of the 

double bond. In the first electronic 

excited state,the double-bond charac- 

Scheme 68. Axially 

chiral 1-(fluoromethylene)-4-methylcyclohexane 

(109), in 

which rotational 

motion around the 

double bond, initiated 

by an IR frequency followed 

by a UV-frequency 

laser pulse, 

has been studied 

computationally. [327] 

ter is significantly reduced and kinetic 

barriers to rotation are much smaller. 

On excitation to this state by using a 

UV laser,all the kinetic barriers could, 

in principle,be overcome and the 

instantaneous angular momentum at 

the moment of excitation preserved. A 

well-timed excitation pulse should 

therefore be able to select the direction 

in which rotation will continue in the 

excited state. Once again,if relaxation 

effects are taken into account,this 

rotation will soon be retarded and will 

certainly stop on return to the ground state. A timely return to 

a repulsive region on the ground-state surface,however,may 

be able to maintain the motion and allow a second cycle of 

excitation to be applied. The use of two electronic states of a 

double bond to generate unidirectional rotation can be 

related back to the directional motors from the Feringa 

research group,discussed in Section 2.2. 

As shall be discussed extensively in Section 8,the 

incorporation of molecular machines into ordered phases, 

such as at interfaces or in liquid crystals,is an important goal 

in current research. Crystalline solids,however,present a very 

different environment within which to explore submolecular 

motions. [328] The combination of crystalline order with 

addressable molecular motions,to yield so-called “amphidynamic” 

crystals,provides a novel and challenging situation for 

the operation of artificial molecular machines. To this end, 

Garcia-Garibay and co-workers have initiated a detailed 

investigation of the gas-phase and solution-phase dynamics as 

well as the solid-state packing and dynamics of a series of 


Chemie 

molecules such as 110–113 (Scheme 69). [329,330] It is intended 

that the bulky trityl- (110, 112,or 113) or triptycyl-derived 

(111) portions (blue) should form the lattice framework and 

remain static,while rotation of the phenylene (110, 111,or 

Scheme 69. Molecular “gyroscopes”. [329,330] A selection of rotor structures 

constructed with the intention of demonstrating controllable 

molecular-level motion in crystalline solids. The bulky components 

colored blue are intended to direct the formation of ordered crystalline 

arrays in which free volume around the rotator section (red) results in 

low barriers to rotation. 

113) or diamantane (112) rotator (red) is the single internal 

degree of freedom. The arrangement of a central rotator 

spinning within a framework which shields it from external 

contracts can be compared to a macroscopic gyroscope. [331] 

Key to the desired dynamics is the volume-conserving nature 

of the conformational process,together with the ability of the 

bulky framework to force packing arrangements which allow 

free volume around the rotator unit. The construction of 

analogues in which the central rotator contains a dipole is 

intended to create systems in which the motion can be 

controlled by an external electric field. [329d] The thermal solidstate 

dynamics of one such example, 113 (DG ° 

13 kcal 

mol 1 for fluoroarene spinning),have been studied by both 

NMR and dielectric spectroscopies, [329j] while dynamic studies 

of the nonpolar analogues suggest that significantly lower 

barriers to rotation are obtainable on suitable functionaliza- 


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Reviews 

tion of the static framework, [329e,330a] or on incorporation of 

rotators with higher symmetry,as in 112. [329i,332] 

A series of fully encapsulated gyroscope structures have 

been prepared and studied in solution by Gladysz and coworkers. 

[333] The crystal structure of 114 indicates that 

sufficient free volume around the rotator should exist to 

permit a low barrier to rotation in the solid state (Scheme 70). 

Scheme 70. Fully encapsulated “gyroscope” structures 114 and 115. [333] 

Reduced-symmetry derivative 115,which also possesses a 

dipole moment as a possible handle to externally control the 

motion,allowed the rotational motion to be observed in 

solution. However,the activation barrier for the process was 

found to be not insignificant (DG ° 

11 kcalmol 1 ). [333] As 

was noted in Section 1.2.2,the effects of friction and thermal 

noise are extremely important on the molecular scale,but it is 

proposed that conditions may ultimately be found in which 

they are reduced to the extent that inertia in encapsulated or 

solid-state rotors becomes significant. 

Supramolecular crystalline structures offer a different 

approach to solid-state rotors. The crown ethers in the tripledecker 

supramolecular cation [Cs2([18]crown-6) 3] 2+ undergo 

rotational motion above 220 K in a crystalline environment 

with paramagnetic [Ni(dmit) 2] counterions (dmit 2 = 2thioxo-1,3-dithiole-4,5-dithiolate). 

[334] 

Furthermore,the 

motion is strongly coupled with the magnetic properties of 

the crystal,thus suggesting one potential control mechanism. 

It has already been demonstrated that the application of 

pressure to the crystal can retard or even stop the thermally 

driven motion. [334] 

6. Self-Propelled “Nanostructures” 

The self-propulsion of microscopic objects has fascinated 

scientists from a range of backgrounds for well over a century. 

Spontaneous physical phenomena such as “tears of wine” and 

the motion of “camphor boats” engaged the minds of many 

eminent 19th century scientists,while the advent of microscopy 

revealed the deterministic motion of microorganisms to 

the biological community. Two distinct mechanisms—interfacial 

and mechanical—can be discerned in these natural 

phenomena and attention has recently turned to artificial 

devices,ultimately of molecular size,which can achieve the 

same results. [335] Just like the machines in Section 5,nanoscale 

self-propulsion devices are not powered by thermal energy. 

Field-driven mechanisms,however,address ensembles of 

molecules,whereas here we look at structures whose movements 

are driven by forces generated between each individual 


machine and the surrounding medium or track. Such 

machines can either operate autonomously—where the 

energy for movement is constantly present—or non-autonomously—where 

the energy must be applied in a series of 

stimuli given in a particular order. 

6.1. Propulsion by Manipulating Surface Tension 

A difference in surface tensions on either side of a liquid 

droplet or gas bubble can cause its directional transport 

through a second liquid or over a solid substrate. [336] This 

phenomenon is known as the Marangoni effect and is 

responsible for a number of naturally observed spontaneous 

processes. [337] In artificial systems,Marangoni flows are 

usually associated with a temperature gradient [336a,338] and 

have been proposed as a means of microfluidic pumping. [339] 

A similar effect can be achieved for a droplet sitting on a 

homogeneous surface if the droplet contains a species which 

adsorbs onto the surface. [340] Droplet motion is then driven by 

the irreversible modification of the surface free energy which 

affects the interfacial energy on either side of the droplet (see 

also Section 8.3.4)—a so-called “chemical” Marangoni 

effect. [341] 

Whitesides and co-workers have reported the autonomous 

movement of millimeter-scale metallic objects at the 

liquid/air interface. [342] On one side,the objects feature a small 

area of platinum metal which catalyzes the decomposition of 

hydrogen peroxide to water and dioxygen. In an aqueous 

solution of hydrogen peroxide,the metallic plates are 

propelled by the recoil force of the oxygen bubbles. Subsequently,Sen,Mallouk,Crespi,and 

co-workers created 

smaller rod-shaped particles consisting of 1-mm-long platinum 

and gold segments. [343] These were suspended within an 

aqueous solution of hydrogen peroxide and again showed 

propulsion which is directly linked to the production of 

oxygen. In contrast to the system developed by Whitesides 

and co-workers,however,movement was found to be towards 

the oxygen-producing platinum region. It appears that the 

oxygen produced adheres to the hydrophobic gold surface in 

the form of nanobubbles,thus setting up a concentration 

gradient along the gold segment as the oxygen diffuses away 

from the platinum regions. It has been proposed that the 

resulting interfacial energy gradient causes motion of the rod 

towards the platinum end. However,the precise details of the 

propulsion mechanism are still a matter of investigation. [335,344] 

The driven and random thermal components of the motion 

could be distinguished at various viscosities for rods operating 

near an aqueous/organic interface. [345] The same technology 

has been used to create a rotational device, [346] while 

incorporation of a ferromagnetic metal into the nanorod 

design has allowed control over the directionality of movement 

by using an external magnetic field. [347] Independently,a 

nanorod system composed of nickel and gold regions has been 

developed by Ozin,Manners,and co-workers which undergoes 

both linear and rotational self-propelled motions in 

hydrogen peroxide (Figure 33),the latter seemingly a consequence 

of the tethering of one end of a rod to a surface 

impurity or defect. [348] 



Figure 33. Optical microscope snapshots of a nickel/gold nanorod 

moving in a linear fashion (1!3) before becoming attached to a 

surface impurity and rotating counterclockwise (4!6). [348] Reprinted 

with permission from Ref. [348]. 

All these devices are both autonomous 

and catalyst-based,which means 

that,unlike a camphor boat or a chemical 

Marangoni droplet,they do not have 

to carry a finite supply of “fuel” onboard. 

Clearly,however,they are not yet 

molecular in nature. Recently Feringa 

and co-workers tethered a synthetic 

dinuclear manganese catalase mimic to 

a silica microparticle and again observed 

motion powered by the decomposition 

of hydrogen peroxide. [349] Although 

functionalization of the microparticle is 

theoretically homogeneous,defects 

result in inhomogeneous bubble nucleation,thus 

providing the asymmetry that 

gives rise to directional powered movement. 

Even though the mechanism of 

propulsion in this case is not yet clear,it 

demonstrates that the catalytic domain 

of a self-propelled motor can be scaled 

down to a molecular size. It remains to 

be seen if there is a lower limit to the 

particle size for which these types of 

strategies are practical (in all current 

systems,the movement of particles less 

than a micrometer in length is indistinguishable 

from Brownwin motion),what 

fidelity of directionality is possible (particularly 

for small particles where Brownian 

motion becomes significant),and 

whether or not it is possible to constrain the medium to a 

track along which the particle moves (for example,by 

confining the fluid to a microscopic capillary). 

6.2. Mechanical Self-Propulsion—Molecules that Can Swim? 


Chemie 

Most microorganisms use a different mechanistic 

approach to self-propulsion which is more akin to the 

mechanical swimming of an animal or propulsion of a 

macroscopic boat. However,the low Reynolds number at 

small length scales (see Section 1.2.2) puts constraints on the 

nature of productive swimming mechanisms. [350] This was 

probably first considered from a physical perspective by 

Purcell,who deduced that any useful mechanical mechanism 

must involve a nonreciprocal motion which breaks the timereversal 

symmetry. [27] Since the mechanism needs to be 

repetitive,this effectively corresponds to the requirements 

of a molecular-level motor in which the substrate is the 

components of the machine itself (Sections 1.4.2 and 4.4). 

Purcell proposed a simple way in which this could be 

achieved: utilization of a “swimmer” composed of three 

rigid parts,linked by two hinges (Figure 34 a). This device has 

recently been examined quantitatively [351] and reduced to a 

simpler one-dimensional problem by replacement of the 

hinges by simple springs (Figure 34b). [352] A number of other 

Figure 34. a) Nonreciprocal sequence of configurations for Purcell’s three-link swimmer, which could 

result in propulsion at low Reynolds number. [27,351] b) A one-dimensional relative of Purcell’s three-link 

swimmer. [352] c) Possible nonreciprocal motion in a three-part, two-hinge molecule. d) Possible nonreciprocal 

motion in a two-part, one-hinge molecule: cis–trans isomerization of an imine. [356] 


133

Reviews 

swimming mechanisms involving nonreciprocal motion have 

also been investigated theoretically from the dual perspectives 

of modeling biological phenomena and designing microscopic 

devices. [353] Somewhat surprisingly (and perhaps analogous 

to the lack of molecular designs based on fluctuationdriven 

transport mechanisms),despite a recent success in 

creating a microscopic swimmer which operates by nonreciprocal 

motion, [354] there appears to have as yet been no 

investigation of such mechanisms at the molecular level. 

Incorporating two orthogonally addressable switches into a 

molecule would give a Purcell-like three-part-two-hinge/ 

spring structure (Figure 34 c). Adding bulk,the cyclodextrin 

in a known rotaxane system, [355] for example,would increase 

the net change in the position of the mass. However,the 

requirements of stimuli-induced nonreciprocal nanoscale 

motion for a low Reynolds number swimmer could also 

potentially be fulfilled by a two-part-one-hinge/spring molecule,by 

using a chemical reaction that can be reversed by a 

different nuclear pathway to the original transformation; for 

example,the photoisomerization and thermal reisomerization 

of certain imines [356] (Figure 34d). Other mechanical molecular 

switches discussed elsewhere in this Review are plausible 

candidates for linear mechanisms of the type shown in 

Figure 34 b. The major problem with the realization of any 

of these systems in a working molecular form will be carrying 

out the stimuli-fueled motions fast and frequently enough so 

that they are not swamped by the background Brownian 

motion. 

Repetitive directional rotation of any chiral object is,of 

course,also a nonreciprocal motion. Field-driven unidirectional 

rotation of a chiral molecular rotor (Section 5) which is 

not confined to a surface through any stator unit could result 

in its propulsion through a liquid in direct analogy to a screw 

propeller on a boat or the bacterial flagellar system. This 

situation has been studied theoretically with a view to using 

circularly polarized microwaves to spatially resolve a racemic 

mixture of “propeller-shaped” molecules. [357] It has been 

postulated that anchoring such rotors at a fixed location 

within a fluid could theoretically create a microfluidic 

pumping system. [312] 

7. Molecular-Level Motion Driven by Atomically 

Sharp Tools 

The development of STM [358] and AFM [359] has dramatically 

shifted the goalposts for what it is possible to see,and 

potentially do,with synthetic molecular machines. For the 

first time these instruments offer scientists the opportunity to 

both observe and manipulate atomic and molecular events 

that operate not on ensemble-averaged populations of species 

but on single chemical entities. [360,361] 

The early STM manipulations of single atoms and 

molecules had to be carried out at extremely low temperatures 

to suppress thermal motion. In one famous example,a 

single-atom electronic switch was created by using STM,with 

its operation based on changing the position of a xenon atom 

relative to two electrodes. [362] The manipulation of organic 

molecules requires careful balancing of adsorbant–adsorbate 


interactions: molecule–substrate binding must be strong 

enough to prevent thermal motion at the temperature used, 

but not so strong that rupture of covalent bonds results 

instead of translation across the surface. [360e,f] These criteria 

were first met at room temperature in 1996 with porphyrin 

116 (Figure 35). [363] In the gas phase,and on a Cu(100) surface, 

Figure 35. a) Porphyrin 116 for which positioning was induced at room 

temperature on a Cu(100) surface by the STM tip. [363,364, 366] b) Decacyclene 

117, for which STM-tip-switched, thermally driven rotations are 

observed on a Cu(100) surface at coverages just below one monolayer 

(c and d). [374] Both molecules adsorb on the surface through the 

appended tert-butyl groups, with the main planar skeletons in the 

plane of the substrate. c) and d) Constant-current STM images of a 

clean Cu(100) surface with a submonolayer coverage of 117. Stationary 

molecules appear as a circular arrangement of six lobes (arising from 

the six tert-butyl groups) and gaps in the monolayer appear as dark 

regions. In (c), the marked molecule is at a gap in the monolayer but 

it is aligned with the lattice and therefore stationary. In (d), the same 

molecule has been moved a distance of 0.25 nm by the STM tip and is 

no longer bound tightly by its neighbors and it therefore rotates, which 

is observed as a blurring of the lobed structure. The STM images are 

reprinted with permission from Ref. [374]. 

the di-tert-butylphenylene substituents are oriented perpendicular 

to the porphyrin unit and act as relatively sticky “legs” 

which separate the polyaromatic core from the surface, 

thereby fixing the molecules securely in place while modulating 

the extremely strong interaction of the planar central core 

with the substrate. [364] Pushing with an STM tip causes 

translational motion,which is facilitated by accompanying 

random rotations or “chattering” of the phenyl rings,which 

lowers the barrier to movement. [363,365,366] 

Interlocked architectures provide another means through 

which the correct balance of forces can be achieved, 

ultimately enabling submolecular co-conformational changes 

to be made in a single molecule. An early report on STM 

imaging of a benzylic amide [2]catenane deposited from 

solution onto highly oriented pyrolitic graphite (HOPG) 

showed rather weak adsorption on the surface. [367] A much 



larger [2]catenane was subsequently shown to form a tightly 

packed polycrystalline arrangement on the same surface,with 

the larger number of aromatic functionalities and greater 

flexibility leading to stronger adsorption. [368] Co-conformational 

motion in an interlocked architecture was achieved 

when an STM tip was used to reversibly move one or two 

adjacent cyclodextrin rings along the polyethylene glycol 

derived thread in a polyrotaxane adsorbed on MoS 2 

(Figure 36). [369] This abacus-like motion is reminiscent of an 

earlier report on the positional manipulation of C 60 molecules 

on Cu(111) surfaces,where the thermal motion of these rather 

poorly adsorbed species is restricted by confinement to a 

monatomic step edge. [370] 

Figure 36. Translocation of a cyclodextrin ring in a polyrotaxane 

induced by a scanning probe. [369] The ring (indicated by a yellow arrow) 

is moved first towards the left (a!b) then back to the right (b!c). 

The white box on image (a) indicates the region of detail which is 

magnified in (b) and (c). Reprinted with permission from Ref. [369]. 

An STM tip has been used to apply a localized voltage to a 

thin film of bistable [2]rotaxanes which has resulted in 

conductance switching. [371] Based on the behavior of similar 

molecules in other solid-state experiments (see Section 8.3.1) 

it is proposed this effect is due to macrocycle shuttling 

triggered by tip-induced oxidation of the thread. A similar 

single-molecule switching phenomenon has been observed for 

an oligopeptide organized in a self-assembled monolayer. The 

peptide adopts one of two helical conformations depending 

on the polarization of the STM tip and the two states are 

characterized by different molecular heights and conductances. 

[372,373] 

STM-induced single-molecule positional switching has 

been employed to reversibly control thermally driven motions 

on surfaces. [374] At monolayer coverage on Cu(100),decacyclene 

117 forms a two-dimensional van der Waals crystal, 

while at coverages significantly below one monolayer, 

random thermal motions are extremely fast and not observable 

by STM. When coverage is a little less than a full 

monolayer,however,the 2D lattice has small gaps or “nanocavities” 

(Figure 35c,d). The molecules at the borders of these 

free spaces can sit in one of two positions: a highly symmetrical 

one,following the order of the adjacent lattice,or a 

less symmetrical one. Movement between these two sites can 

be effected by the STM tip. In the less symmetrical site,the 

molecule is still constrained by its neighbors,but is disengaged 

from some of the intermolecular interactions,so that it freely 

rotates in a random fashion at high speeds (Figure 35 d). [374,375] 

It has been noted that in the “engaged” state the potentialenergy 

profile for rotation is asymmetric,thus suggesting that 

such a system could be a starting point for a unidirectional 


Chemie 

rotor. To date,however,there have been no further reports on 

the incorporation of the remaining features necessary for such 

a system. [376] 

While STM permits the manipulation and observation of 

complex molecular species adsorbed on conducting surfaces, 

AFM can be used to image nonconducting surfaces and can 

operate under ambient conditions,even on samples in 

solution. The use of an AFM cantilever as a force sensor or 

applicator (so-called “force spectroscopy”) has facilitated 

some remarkable single-molecule investigations of receptor– 

ligand interactions,of the entropic and enthalpic factors 

involved in biopolymer folding,and of the mechanical 

elasticity of biopolymers. [360j–p] Synthetic polymers are also 

amenable to this approach,although nonspecific forces at 

small tip–substrate separations and the physical size of 

available tips have impeded the application of AFM to 

small-molecule perturbations and measurements to 

date. [360g,i,377] It has recently been discovered that an AFM 

tip can be used to initiate the formation of regular arrays of 

deformations in thin films of simple rotaxanes (Figure 37). [378] 

The effect is unique to films made from interlocked molecules 

(it does not happen to films of the non-interlocked components,for 

example) and is a result of coupled nucleation 

recrystallization being favored by the ease of intercomponent 

mobility for these molecules. The features of the nanoscale 

dot arrays are easily varied by changing the thickness of the 

film,and show potential for application in information 

storage technology. 

Figure 37. a) Array of dots fabricated by individual line scans of the 

AFM tip on a 5-nm-thick film of a benzylic amide [2]rotaxane 89 

(Scheme 51) deposited on HOPG. [378] b) For a given thickness (here 

20 nm), the number of dots is linearly proportional to the scan length. 

The film thickness controls the characteristic size. c) A pattern made 

up of 31 lines with 45 dots each on an approximately 30 ” 30 mm 2 area 

of a thicker film. d) Proof-of-concept for information storage. The 

sequence “ec7a8” in the hexadecimal base corresponds to the 

number 968616. 


135

Reviews 

Despite the advances in the observation and manipulation 

of single-molecule dynamics,it is only recently that potential 

structural precursors for molecular machines specifically 

designed to be actuated at the single-molecule level by 

probe techniques have been investigated. Variations in 

conductance on deformation by atomically sharp probes 

have been reported for a number of molecular species,in 

particular fullerenes. [360s] For example,the angle between the 

porphyrin core and an individual di-tert-butylphenyl leg in 116 

can be reversibly manipulated by either STM or AFM, 

thereby leading to an order of magnitude switching of the 

STM tunneling current between the tip and substrate. [379] The 

low energy requirements of such manipulations make them 

inherently attractive for exploitation in future nanoelectronic 

devices [360t] but they have also inspired the design of structures 

specifically designed to exhibit mechanical switching of 

electrical properties induced by an STM tip. Molecules such 

as 118 (Scheme 71a) have been proposed in which two 

Scheme 71. a) Structure of “lander” molecule 118 in which it is 

intended that manipulation of the angle between the phenyl rotator 

(red) and polyaromatic boards (blue) will control conductance through 

the molecule. [380] As for previous structures, interaction with the 

surface is through the orthogonally oriented di-tert-butyl “legs” (black). 

b) 1,4’’-Paratriphenyldimethylacetone (119) has been chemisorbed on 

a Si(100)-2 ” 1 surface through the oxygen atoms and the manipulation 

of the phenyl rings investigated by STM. [382] The arrows indicate the 

degrees of freedom which were probed with the tip. 

polyaromatic regions (blue) are connected by an aryl rotator 

(red). [380] In analogy to a series of rigid predecessors, [360t,381] the 

polyaromatic core of these molecular “landers” is intended to 

act as a single molecular wire,which is raised and insulated 

from the surface by the di-tert-butylphenyl legs (similar to 

116). If variation in the angle of the central rotator can 

significantly affect conductance through the molecule it 

would constitute a single-molecule nanomechanical electrical 

switch. A clear challenge here is achieving a system where 

thermal rotations of the central rotator do not erase the state 

of the switch while still allowing tip-induced rotation. A 

recent study of simple triphenyl 119 (Scheme 71b),chemisorbed 

through the oxygen atoms to a Si(100)-2 ” 1 surface 

has highlighted some of the problems facing such delicate 


manipulations of intramolecular conformation with an STM 

tip. [382] However,reversible conformational switching of 

biphenyl molecules adsorbed on a Si(100) surface,has been 

successfully realized through electronic excitation using an 

STM tip. [383] Remarkably,two different dynamic processes 

could be initiated simply by positioning the tip at slightly 

different locations over the molecule. 

Investigations into the correlation and manipulation of 

mechanical modes within single molecules on surfaces has 

begun. These early studies highlight the exciting potential for 

successful working systems together with the difficulties 

involved in balancing the forces necessary for a molecule to 

overcome thermal motion while still allowing reversibly 

addressable internal modes. Pushing the 4-tert-butyl “handles” 

(dark blue) with an STM tip was intended to rotate the 

triptycene “wheels” (red) and roll “molecular wheelbarrow” 

120 (Scheme 72) across a surface. [384,385] Simulations of early 

designs did not result in the intended motion on account of a 

Scheme 72. Structure of “molecular wheelbarrow” 120, designed to 

convert a directional translational stimulus applied by the STM tip at 

the “handles” (dark blue) into directional rotation of the “wheels” 

(red). [384–386] 

flattening of the rear legs on the surface. [384a] If this effect was 

eliminated from the simulations,rotation of the wheels still 

did not occur,they simply glided across the surface. On the 

other hand,when second-generation system 120 was adsorbed 

on Cu(100),contact with the STM tip fragmented the 

molecule,thus suggesting strong interactions between the 

molecule and the surface even at room temperature. [386] 

Clearly a macroscopic wheelbarrow operates on the 

principle that friction between the wheel and the ground is 

greater than resistance to rotation around the axle. Friction is 

a function of the nature of the surfaces in contact and the 

weight of the barrow. At the molecular level,however,the 

concept of friction is less easily understood: [387] the resistance 

to sliding motion arises from individual short-range attractive 

and repulsive forces,as well as longer-range attractive van der 

Waals interactions,while the effect of gravity is negligible. 

Rolling translation on surfaces and the role of friction have 



been considered more extensively in relation to fullerenes 

and carbon nanotubes (see also Section 5) on account of their 

spherical and cylindrical shapes. [388] It has now been demonstrated 

experimentally that both carbon nanotubes [389] and 

C 60 [390] can undergo tip-induced surface translations through a 

rolling mechanism in preference to sliding motions. This has 

recently been exploited by Tour and co-workers in a 

remarkable demonstration of what they term a singlemolecule 

“nanocar”, 121 (Figure 38a). [391] The molecule 

consists of an oligo(phenylethylene) “chassis” supporting 

four C 60-derived “wheels”. These molecules can be imaged on 

Au(111) by STM as four bright lobes that are stationary at 

room temperature. Increasing the substrate temperature 

results in 2D movement of the molecules,observed through 

sequential STM images (Figure 38c–g). The orientation of the 

molecules can be determined because of the difference in the 

length and width dimensions,and translational motion clearly 

occurs perpendicular to the axles,with pivoting around one 

wheel accounting for changes in direction. This orientation 

strongly suggests a thermally driven rolling mechanism,and 

was confirmed by the behavior of two three-wheeled analogues,one 

of which (122,Figure 38b) was designed only to 

undergo pivoting,the other of which could not sustain any 

motions involving concerted rolling of all the wheels (not 

shown). Movement of 121 could also be achieved by 

manipulation with the STM tip,but again only motion 

perpendicular to the axles was facile. Intriguingly,this 

motion was generated with the tip in front of the molecule, 

pulling it along,in contrast to most other examples of tipinduced 

molecular movements. The authors propose that 

Figure 38. a) Chemical structure of four-wheeled “nanocar” 121. [391] b) Chemical structure of the three-wheeled analogue 122 with an axle 

arrangement designed to allow only pivoting motion through correlated rolling of the fullerene wheels. c)–g) STM images of 121 rolling on 

Au(111) at 2008C. The orientation of 121 can be determined by the wheel separation. Images (c)–(g) were selected from a series spanning 

10 min. h) Schematic representation of the motions of 121 and 122. For clarity the alkoxy substituents have been omitted. The STM images (c)– 

(g) and the schematic representation (h) are reprinted with permission from Ref. [391]. 


Chemie 


137

Reviews 

ultimately ensembles of such molecules could be propelled by 

external fields (see Section 5). [391] 

Cyclic molecules in which a position of unsaturation 

moves around equivalent positions through sigmatropic 

rearrangements (see Section 2.1.5) have been proposed as 

being able to roll across surfaces,powered by the breaking 

and formation of substrate–molecule bonds around the 

ring. [392] A related phenomenon has been observed experimentally 

by STM when a fluorinated C 60 derivative was 

deposited on Si(111)-(7 ” 7). The fullerenes were observed to 

move across the surface leaving a trail of fluorine atoms in 

their wake—presumably the result of a rolling motion 

powered by chemisorption of fluorine to the surface (somewhat 

reminiscent of the “chemical” Marangoni motion of 

droplets containing surface-active species,Section 6.1). [393] 

Random surface motions of adsorbates can be directed 

along specific directions on low-symmetry surfaces. [394] 

Recently,however,STM was employed to observe the 

directional diffusion of a chemisorbed molecule (9,10dithioanthracene) 

on a high symmetry Cu(111) surface. [395] 

A size mismatch between the molecular dimensions and 

surface periodicity results in sequential motion of the thiol 

“legs” so that the molecule s orientation is always maintained. 

Scanning probe microscopies also open up opportunities 

to design machines that operate and generate an output at the 

single-molecule level without being powered by direct 

manipulation by the probe tip. Electroactive organometallic 

rotor 123 (Figure 39) has been designed to function on a 

surface,attached through derivatization of the hydrotris(indazolyl)borate 

ligand (red) leaving the cyclopentadienyl 

ligand (blue) free to rotate. [385,396] The proposed mechanism 

for driven directional rotation envisages a single-molecule 

electronic junction through which selective oxidation of one 

ferrocene moiety occurs. Anodic repulsion of the resulting 

cation moves the charge towards the cathode where it is 

reduced,the rotation bringing the next ferrocene unit close to 


the positive terminal for oxidation. It is not yet clear if such an 

experimental set-up is achievable or whether direct electron 

tunneling from the cathode to the anode would result instead 

or even whether thermal motion would scramble the rotor s 

position. Indeed,the low-energy barrier demonstrated for 

rotation around the ruthenium–cyclopentadienyl bond [397] 

requires that the electrostatic driving forces be significant at 

all times during the mechanism to avoid thermal scrambling. 

An alternative approach may be to bias rotation using a 

perpendicularly aligned electric field. 

Other techniques besides scanning probe microscopies 

allow the application of external fields (Section 5) for both 

imaging and manipulation with molecular-scale precision. 

Magnetic tweezers,glass microneedles,and,perhaps most 

prominently,optical tweezers have been used to investigate 

the mechanical behavior of biomolecules. [398] Many of the 

most significant advances with optical tweezers have been in 

the study of molecular motor proteins,the optical trap 

allowing monitoring and application of forces to motors and 

their subunits at various stages in their operation. This 

technique has also been applied to protein folding and 

unfolding,binding events,and DNA transcription. One of the 

most striking demonstrations of the capabilities of this tool is 

the tying of a knot in an actin strand,thereby determining 

significant mechanical properties of the filament. [399] 

Recently,a light pattern incident on an photoconductive 

surface was used to set up non-uniform electric fields which 

allow parallel trapping and manipulation of multiple particles 

over a large area—essentially a molecular-level example of 

dielectrophoresis. [400] Various methods for detecting single 

fluorophore molecules have been developed,thus leading to 

new insights in many biophysical investigations. [401] Together, 

all these tools for probing dynamic events,interactions,and 

processes at the single-molecule level have had a profound 

effect on the understanding of many biological systems. The 

ability to examine single entities as opposed to ensemble 

Figure 39. a) Chemical structure of a potential molecular motor designed to operate at the single-molecule level. [385, 396] b) Proposed mechanism of 

operation: 1) a potential difference applied across a nanojunction results in oxidation of the ferrocene group nearest the anode (2); electrostatic 

repulsion results in rotation so as to bring the ferrocenium cation towards the cathode where it can be reduced (3); simultaneously a new 

ferrocene unit is brought close to the anode where it is oxidized (4), to generate a rotational isomer of (2). Fc = ferrocene; Fc + = ferrocenium. 



averages has allowed the study of phenomena in a manner not 

possible with a nonsynchronized population of molecules. We 

look forward to the increased application of these powerful 

techniques to synthetic molecular motors and machines over 

the next few years. On the other hand,as the design and 

mechanistic complexity of synthetic devices grows,so more 

demanding questions will be asked of analytical techniques. 

Accordingly,the quest for new techniques for addressing and 

analysis on the nanoscale continues apace. Very recently,for 

example,the creation of an optical “superlens” was reported 

which breaks the diffraction limit in optical microscopy and 

allows imaging of objects significantly smaller than the 

wavelength of light used. [402] The resolution of the new lens 

is 60 nm,but this work points the way for progression towards 

truly nanoscale optical microscopy. 

8. From Laboratory to Technology: Towards Useful 

Molecular Machines 

8.1. The Current Challenges: Constraining, Communicating, 

Correlating 

Although the development of reaction-driven,fielddriven,self-propelled,and 

scanning-probe-controlled submolecular 

motion is rapidly gathering pace,it is the design and 

synthesis of molecular structures—both classical covalent and 

mechanically interlocked—which restrict the thermal movements 

of various submolecular components that has been 

central to the major advancements in molecular-level 

machines to date. These structural constraints have been 

successfully combined with external switching of molecular 

and/or electronic structure to create systems which exhibit a 

remarkable level of control over both the relative position of 

units as well as the frequency and even directionality of their 

motion. Whatever the application or the precise mode of 

action,however,it is clear any practical device requires that 

the molecular machine is able to interact with the outside 

world,either directly through macroscopic or nanoscopic 

property changes or through further interactions with other 

molecular-scale devices. The problem of how to “wire” 

molecular machines together and to the outside world also 

has implications for the physical construction of the devices 

which,in turn,puts further demands on the fidelity of the 

molecular-level mechanical processes over a range of conditions. 

In the following sections,we examine research that 

addresses these challenges by focusing on using molecularlevel 

motion to produce a functional property change or 

perform a physical task. 

Nature s motors and machines generally work at interfaces 

or on surfaces and the transfer of molecular-machine 

technology onto solid substrates is a key step in the development 

of many potential applications. Not only do solutionphase 

systems pose problems in terms of integration with 

current technologies,directly transmitting mechanical 

changes at the molecular level to the macroscopic world will 

generally require organization and cooperation of many 

molecular-level machines. There are already several examples 

of switchable and detectable supramolecular recognition 


Chemie 

events (including threading and dethreading of pseudorotaxanes) 

which occur at surfaces. [403,404] The current state-of-theart 

in this regard is well represented by Stoddart,Zink,and 

co-workers,who have harnessed the photochemically triggered 

dethreading of a surface-mounted pseudorotaxane to 

release molecules trapped in nanoscopic pores on the same 

surface. [405] 

The problem of achieving controlled movement within 

surface-mounted or solid-state interlocked molecules is more 

demanding,however,with both components constrained to 

the solid support or interface at all times. The first evidence 

for externally stimulated submolecular motions of a catenane 

in the solid state was observed when a vacuum-evaporated 

thin film of a benzylic amide [2]catenane was subjected to 

oscillating electric fields and produced an unexpected secondorder 

nonlinear optical effect. [406,407] In earlier studies,thin 

films of a metal-templated polyrotaxane were deposited on a 

carbon electrode by electropolymerization of pyrrole 

rings. [408] Each rotaxane monomer contained the three binding 

motifs present in [2]catenate [Cu(98)] (Scheme 60a, 

Section 4.6.1). Electrochemical reduction of the pentacoordinate 

Cu II species resulted in pirouetting of the macrocycle 

around the thread to give the Cu I co-conformer in its lower 

energy tetrahedral geometry. The motion was slow,however, 

taking 24 h to go to completion,and oxidation back to Cu II did 

not result in any detectable submolecular motion (the dpp- 

Cu II !terpy-Cu II transition is known to be slower in solution, 

see above). The same kind of motion was attempted in a 

catenate attached to a gold surface through S Au bonds. 

However,in this case no motion could be observed at all. [409] 

Electrochemically induced shuttling has been carried out 

on self-assembled monolayers (SAMs) of [2]rotaxane 124 on 

gold wire immersed in an electrolyte solution (Scheme 73). [410] 

The shuttle features TTF (green) and DNP (red) stations,and 

voltammetry measurements consistent with reversible translation 

of the macrocycle were observed on oxidation and 

subsequent reduction of the TTF unit. A related [2]rotaxane 

organized in Langmuir films undergoes shuttling induced by 

adding a chemical oxidant to the aqueous subphase. [411] 

Evidence for the submolecular motion was garnered from 

comparison of the p-A isotherms of the shuttle film with those 

of control compounds. X-ray photoelectron spectroscopy 

(XPS) of the initial and the oxidized films transferred onto 

solid substrates as Langmuir–Blodgett (LB) monolayers also 

confirmed a change in the position of the ring which was 

consistent with shuttling. 

A different redox-active molecular shuttle was successfully 

oriented perpendicular to the surface of a titanium 

dioxide nanoparticle through attachment to a tripodal 

phosphonate unit at one end of the thread. [412] The use of 

nanoparticles as a support allowed characterization of the 

dynamic processes in the surface-mounted species by both 

1 H NMR spectroscopy and cyclic voltammetry. Redox-triggered 

shuttling of the macrocycle was observed,although not 

with the expected switching characteristics. Paramagnetic 

suppression spectroscopy (PASSY),a novel NMR technique, 

suggests that the shuttling process,at least in solution,in these 

examples is complicated by various folded conformations of 

the thread. [413] 


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Reviews 

Scheme 73. An electrochemically switchable [2]rotaxane immobilized as a SAM on a gold wire. [410] 

Taking advantage of the distinct “rotator” and “stator” 

design of the second-generation overcrowded alkene rotary 

motors (Scheme 22,Section 2.2),Feringa and co-workers 

have anchored these molecules on gold nanoparticles through 

two thioalkyl substituents appended to the base unit. [414] The 

photochemical and thermal rotation was monitored by CD 

spectroscopy and also by differentiation of the two thioalkane 

tethers with an isotopic label,followed by cleavage of the 

motor molecules from the surface at various stages and 

analysis in solution by NMR spectroscopy. [415] 

8.2. Reporting Controlled Motion in Solution 

Like other types of molecular switch, [151] a change in 

property induced by submolecular motion in a molecular 

machine could potentially be used in an information-storage 

or other switching device. The fundamental requirements for 

mechanical systems are the same as their nonmechanical 

counterparts and include: 1) a useful and detectable difference 

between two states; 2) fatigue resistance; 3) stability of 

each state under the operating conditions; 4) fast response 

times; and,particularly for memory applications,5) nondestructive 

read-out. [151] The first of these is rather open to 

interpretation. A change in the chemical shift of an NMR 

signal,for example,may be considered by a chemist to be 

both easily detectable and useful—and there is no reason why 

such outputs might not be technologically relevant in certain 

applications one day. However,most of the examples highlighted 

in this section are chosen in view of the technological 

advantages of particular output modes: optical,electronic, 

and mechanical. This indeed reflects the research direction of 

the field of molecular machines over the past five years,in 

which the interaction of the machine with the outside world 

has become an increasingly important design element. 

8.2.1. Conformational Switches in Solution 


The stimuli-induced cessation of conformational motions 

(“molecular brakes”,discussed in Sections 2.1.2 and 2.1.3) can 

be employed for switching applications. Glass and Raker have 

developed sensors by using a “molecular pinwheel” architecture 

(for example, 125,Scheme 74) which exploits positive 

allosteric binding effects achieved in molecular brakes with 

multiple binding sites (for example,metal porphyrinate 

sandwich compound 22,Scheme 7,Section 2.1.3). [416] Each 

trityl unit has one blade functionalized with a fluorophore and 

the other two with suitable binding sites. The binding of an 

analyte which can bridge between the two trityl moieties 

freezes the rotational motion of the trityl groups with respect 

to each other. The remaining binding sites are now preorganized,thus 

favoring a second,cooperative,binding of the 

substrate. The mode of binding holds the two fluorophores in 

proximity so that an increase in the ratio of the excimer:monomer 

fluorescence can be measured. Pinwheel receptor 125 

is therefore able to detect short dicarboxylates selectively 

over monocarboxylates in aqueous media. [416d] It is proposed 

that this strategy could provide a general means to create 

cooperative sensors through tailoring the binding sites and 

distance between them to be specific for a particular analyte. 

A different approach to mechanically operated sensors is to 

append linear or macrocyclic polyethers to polythiophenes or 

oligothiophenes. In some cases binding can result in a 

significant perturbation to the conformation of the p-conjugated 

system,which results in changes to the molecular 

electronic properties. [417–419] 

The possibility of conformational changes being transmitted 

over relatively long distances through fused cyclic 

frameworks was first noted by Barton in his seminal work on 

the conformational analysis of steroids. [420] An impressive 

example was recently reported by Clayden et al.,who 



Scheme 74. An example of a molecular pinwheel receptor, 125. [416d] Cooperative binding between pairs of convergent binding sites freezes internal 

rotation, thereby bringing the fluorophores into proximity so that the ratio of excimer:monomer fluorescence increases. The combination of 

cooperative binding and a mechanically transmitted binding-induced change in the fluorescence spectrum allows the sensing of short 

dicarboxylates at low concentrations in aqueous solution. 

employed the conformational interactions of aromatic amides 

in 126 to transmit stereochemical information from a chiral 

group to a prochiral reaction site over 25 Š and a minimum of 

23 covalent bonds (Scheme 75). [421] 

Such conformational communication also presents opportunities 

to relay a stimuli-induced conformational change— 

triggered by a stimulus at some receptor site—through some 

Scheme 75. Ultra-remote stereocontrol by conformational communication 

in the reaction of trisxanthene 126. [421] The chiral oxazolidine ring 

(red) imposes a right-handed (P) twist on the adjacent amide as a 

result of both electronic and steric interactions. As the amides in such 

xanthene derivatives strongly prefer all-anti conformations, the effect of 

the enantiopure unit is transmitted throughout the molecule as a 

strongly preferred conformation for all the amide groups. The result is 

that Grignard addition to the aldehyde (green) proceeds with > 95:5 

diastereofacialselectivity. Subsequent cleavage of the oxazolidine 

affords an almost enantiomerically pure (> 90 % ee) alcohol. 


Chemie 

structural framework so as to produce a detectable and 

reversible signal at a remote reporter unit. Pyranose-based 

conformational switch 31,for example,(Scheme 11,Section 

2.1.4) has been adapted to bring together two fluorophores 

through a chelation-induced ring-flip,therefore altering 

the optical properties. [422] Similarly,the W-shaped transoid–transoid 

to U-shaped cisoid–cisoid switching of terpyridine 

derivatives (see Scheme 16,Section 2.1.4) has been 

utilized to create another cation-triggered optomechanical 

switch 127 (Scheme 76). [423] This same strategy has also been 

used to switch the distance between two appended porphyrins,thus 

controlling energy- and electron-transfer processes 

between them. [424] 

One challenge,however,is to transduce a signal over 

longer distances, and for that purpose, 2,3,6,7-tetrasubstituted 

perhydroanthracene 128 was designed and constructed. [425] 

Conformational switching is triggered by metal-ion binding to 

the bipyridyl receptor units (red). The resultant three-ring flip 

separates the pyrene reporter units (blue),thus causing a 

change in fluorescence (Scheme 77). The binding signal is 

relayed over a distance of about 2 nm,while an analogous 

system based on 2,3,6,7-tetrasubstituted cis-decalins operates 

over a shorter distance of 1.5 nm. [426] In a first step towards 

transmitting signals over longer distances,the coupling of two 

such cis-decalin switches has been reported: the conformational 

change in one unit precipitates flipping of the remote 

ring system. [427] 

The conformational bistability of resorcin[4]arene cavitands 

(Scheme 12,Section 2.1.4) has been exploited to create 

a well-defined mechanical switch, 129,in which the distance 

between the extremities of the two “arms” is varied from 

approximately 0.7 nm to about 7 nm by a pH change 

(Scheme 78). [428] The conformational change is used to alter 

the distance between a donor–acceptor dye pair,thereby 

eliciting a major difference in the fluorescence resonance 

energy transfer (FRET) response. 


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Reviews 

Scheme 76. A cation-triggered optomechanical switch. [423] When in the U-shape conformation, charge transfer from the pyrene fluorophores to the 

electron-poor complexed terpyridine (terpy) ligand effectively quenches fluorescence. Pulses of Zn II ions are provided by protonation and 

deprotonation of the N,N-bis(2-aminoethyl)ethane-1,2-diamine (tren) ligand, so that, overall, the system is switched by alternate acid (CF 3SO 3H) 

and base (LiOH) stimuli. 

Scheme 77. Signal transduction by transmission of a conformational change from a receptor unit (red) to a reporter (blue). [425] 

8.2.2. Co-conformational Switches in Solution 

The principles of shuttling in metal-templated rotaxanes 

have been extended to create a dimeric system in which the 

submolecular motion results in lengthening and contraction 

of the molecule in a manner reminiscent of the operation of 

the actin–myosin complex,which is the basis of natural 

muscle. [191v,429] Each monomer (130,Figure 40) consists of a 

bidentate dpp site incorporated in a macrocycle (see 98, 

Section 4.6.1) connected to a thread which also contains a 2,9dimethylphenanthroline 

(dmp) ligand and a tridentate terpyridine 

(terpy) site. The Cu I ions used to template formation 

of the dimer coordinate to the dpp unit of one monomer and 

the dmp moiety of the other to give the threaded structure 

[Cu 2(130) 2] 2+ (Figure 41). Unfortunately,electrochemical 

oxidation to the Cu II species did not trigger a change in coconformation; 

even this unfavorable geometry for divalent 

copper ions is too kinetically stable. However,demetalation 

(excess KCN,room temperature,3 h) to give the free ligand 

system 130 2,followed by insertion of Zn II ions (Zn(NO 3) 2, 

room temperature,1 h) generated the contracted form 

[Zn 2(130) 2] 4+ ,a length change of approximately 85 Š to 

65 Š (a reduction of 24 %). The molecule could be returned 


to its original length simply by treatment with excess 

[Cu(CH 3CN) 4]PF 6. 

Simple monomeric stimuli-responsive molecular shuttles 

offer a generic approach to mechanical molecular switches for 

distance-dependant properties through suitable functionalization 

of the macrocycle and one end of the thread 

(Figure 42). [430] 

Following the observation that the positioning of an 

intrinsically achiral benzylic amide macrocycle in relation to a 

chiral center can result in an induced circular dichroism 

(ICD) effect (Section 4.3.1),chiroptical molecular shuttle 

(E)/(Z)-131 was prepared (Figure 43). [431] Unlike chiroptical 

switches in which the presence of,or handedness of,chirality 

is intrinsically altered, [150] (E)/(Z)-131 remains chiral and 

nonracemic with the same handedness throughout; it is the 

expression of chirality that is altered. In the (E)-131 form,the 

macrocycle is held over the fumaramide template and thus far 

from the chiral center of the peptidic station. Correspondingly 

the circular dichroism response is zero,as observed for the 

free thread. In the (Z)-131 maleamide isomer,however,the 

olefin hydrogen-bonding station is “switched off”,the macrocycle 

resides on the chiral peptide station,and a strong 

( 13 000 degcm 2 dmol 1 ) negative ICD response is observed. 



Scheme 78. pH-Governed conformational switching to control a FRET response in resorcin[4]arene cavitand 129. [428] R = n-Hex. 

Figure 40. Monomer unit 130 for the construction of an artificial 

molecular muscle rotaxane dimer. [429] 

The E!Z isomerization is most efficiently carried out by 

irradiation at 350 nm in the presence of a benzophenone 

sensitizer (photostationary state 70:30 Z/E),while the Z!E 

transformation can be achieved almost quantitatively by 

irradiation at 400–670 nm in the presence of catalytic Br 2. 

Although a more modest difference in photostationary states 

is achieved by irradiation at 254 nm (photostationary state 

56:44 Z/E) and 312 nm (photostationary state 49:51 Z/E),a 

large net change (> 1500 deg cm 2 dmol 1 ) in the elliptical 

polarization response is still observed (Figure 43 b) and this is 

reproducible over several cycles without addition of any 

external chemical reagents. [431] 

Figure 41. Reversible switching between extended ([Cu 2(130) 2] 2+ ) and 

contracted ([Zn 2(130) 2] 4+ ) forms in a chemically switched artificial 

molecular muscle. [429] 


Chemie 

A similar approach has been used to create a molecular 

shuttle switch for fluorescence,namely,(E)/(Z)-132 

(Figure 44). [430] This system also relies on the photoswitchable 

fumaramide/maleamide station,but attached to the intermediate-strength 

dipeptide station is an anthracene fluorophore 

while the macrocycle now contains pyridinium units, 

which are known to quench anthracene fluorescence by 

electron transfer. Strong fluorescence (l exc = 365 nm) is 

observed in both the free thread and (E)-132,while shuttling 


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Reviews 

Figure 42. Exploiting a well-defined, large amplitude positional change 

to trigger property changes. [430] a) A and B interact to produce a 

physical response (fluorescence quenching, specific dipole or magnetic 

moment, nonlinear optical properties, color, creation/concealment of a 

binding site or reactive/catalytic group, hydrophobic/hydrophilic 

region, etc.); b) moving A and B far apart mechanically switches off 

the interaction and the corresponding property effect. 

Figure 43. a) Chiroptical switching in the [2]rotaxane-based molecular 

shuttle (E)/(Z)-131. [431] b) Percentage of (E)-131 in the photostationary 

state (from 1 H NMR data) after alternating the irradiation between 

254 nm (half integers) and 312 nm (integers) for five complete cycles. 

The right-hand y-axis shows the CD absorption at 246 nm. 

of the macrocycle onto the glycylglycine station in (Z)-132 

almost completely quenches this emission. At the wavelength 

of maximum emission from (E)-132 (l max = 417 nm) there is a 

remarkable 200:1 difference in intensity between the two 


Figure 44. A fluorescent molecular switch based on [2]rotaxane molecular 

shuttle (E)/(Z)-132. [430] a) Interconversion between fluorescent (E)- 

132 and nonfluorescent (Z)-132; b) images of cuvettes containing 

solutions of (Z)-132 and (E)-132, respectively (0.8 mm, CH 2Cl 2), illustrating 

the clearly visible difference in fluorescence intensity. The 

photograph was taken while illuminating the samples with UV light 

(365 nm). 

states which is strikingly visible to the naked eye (Figure 

44b). [432] 

A related strategy has been applied by Tian and coworkers 

to achieve fluorescence switching in a different type 

of [2]rotaxane system,(E)/(Z)-133 (Scheme 79). [433] In (E)- 

133·2 H,the a-cyclodextrin ring sits preferentially over the 

trans-stilbene unit and this co-conformation is apparently 

further stabilized by strong hydrogen-bonding interactions 

between hydroxy groups on the cyclodextrin 3-rim and the 

isophthaloyl stopper group. [434] As for previous a-CD-based 

rotaxanes (Scheme 33,Section 4.3.1),photoisomerization of 

the stilbene unit can only occur when thermal motion has 

moved the ring away from the binding site. However,the 

strength of the combined hydrophobic and hydrogen-bonding 

interactions (even in water) for (E)-133·2H means that the 

shuttle is effectively conformationally locked: irradiation at 

355 nm,which should isomerize the stilbene moiety,results in 

no change to the system. Formation of the disodium salt of the 

isophthaloyl group (giving (E)-133·2Na) breaks the hydrogen-bonding 

network and although NMR studies show that 

the cyclodextrin continues to sit over the stilbene station, 

enough thermal motion is now present to allow photoisome- 



Scheme 79. Photoswitched shuttling in [2]rotaxane (E)/(Z)-133·2Na which results in fluorescence enhancement 

of the 4-aminonaphthalimide group. [433] The photoisomerization process is prevented when the free 

carboxylic acids of the isophthaloyl stopper are present ((E)-133·2H). 

rization to give (Z)-133·2Na (photostationary state 63:37 

Z/E). In the Z isomer the cyclodextrin ring is forced to reside 

over the biphenyl group. The translocation of the ring is 

accompanied by a 46 % increase in fluorescence intensity of 

the 4-aminonaphthalimide stopper (l max = 530 nm). This 

change is attributed to a restriction of the vibrational and 

rotational movement of the methylene and biaryl linkages 

thus disfavoring nonradiative relaxation processes. The shuttling 

and fluorescence changes are reversible on reisomerization 

to (E)-133·2 Na at 280 nm. 

Using either a stilbene [50k] or an azobenzene [435] configurational 

switch,the same research group have extended this 

concept to [2]rotaxanes in which the fluorescence of either 

one of two different fluorophores can be enhanced depending 

on the position of the ring. [436] Incorporating two different 

configurational switches into such a rotaxane has allowed the 

creation of a molecular system capable of carrying out the 

function of a half-adder—a two-input,two-output device 

which combines AND and XOR logic functions and which 

can perform binary addition. [355] [2]Rotaxane 134 can be 

reversibly switched between four different configurational 

isomers through selective photochemical and thermal stimuli 

(Scheme 80). For operation as a logic gate,UV irradiation at 

380 nm and 313 nm can be considered as two input signals (I1 

and I2). In both (Z N=N,E C=C)-134 and (E N=N,Z C=C)-134,the 

proximity of the ring to one or other stopper increases its 

fluorescence by an appreciable amount,while in both (E,E)- 

134 and (Z,Z)-134 the cyclodextrin is not held close to either 

fluorescent stopper (because of rapid shuttling in the former 

case and trapping on the biphenyl unit in the latter). 

Therefore,if the change in fluorescence intensity relative to 

(E,E)-134 (DF) is taken as an output (O1),this can be 

interpreted as an XOR gate (see truth table in Scheme 80). 

All four states exhibit absorbance maxima at 270 nm,which is 

found to increase in intensity on successive E!Z isomer- 

ization of the double bonds, 

and at 350 nm,which 

decreases as E!Z for each 

configurational switch. The 

result is that the difference 

in the absorption at these two 

wavelengths,expressed as a 

fraction of the absorption at 

the isobestic point (301 nm), 

is relatively small for all but 

the (Z,Z)-134 isomer and, 

thus,this value can be considered 

the output of an AND 

gate (O2). As these two functions 

operate in parallel,are 

based on the same two inputs, 

and give two distinct outputs, 

this system represents monomolecular 

realization of a 

half-adder function operating 

purely through photonic stimuli. 

[252,355] It is also possible to 

construct a [3]rotaxane analogue 

of 134. [437] The resulting 

shuttle exhibits three stable states (E,E-, Z,E-,and E,Z-) each 

of which exhibits a different fluorescent response as a 

consequence of the position of the rings. 

The nature of interlocked architectures—in which certain 

functional groups are encapsulated by the binding cavity of a 

separate unit—suggests that their dynamic attributes may 

allow the development of novel applications in catalysis. As a 

first step towards creating a fully processive catalyst,Rowan 

and co-workers have created a macrocyclic unit incorporating 

a manganese porphyrin,which can catalyze the epoxidation of 

an olefin bound in the inner cavity when an external oxidant 

and a bulky ligand are also present. [438] Threading this unit 

onto a polybutadiene chain and stoppering to create a 

rotaxane architecture creates a mechanically linked catalyst–substrate 

system; when the external reagents are added, 

the macrocycle promotes epoxidation at multiple positions on 

the thread,although at present the movement and action of 

the macrocycle is presumably random and nondirectional 

between thread sites. [439] The mechanically linked nature of 

such catalyst–substrate complexes could lead to processive 

catalysts for the post-polymerization modification of polymers 

and provide insight into the operation of the processive 

enzymes which are so central to fundamental processes in the 

cell. 

8.3. Reporting Controlled Motion on Surfaces, in Solids, and 

Other Condensed Phases 


Chemie 

Early successes at operating molecular machines on 

surfaces and at interfaces were discussed in Section 8.1. 

Incorporation of mechanical switches (Section 8.2) into such 

environments can lead to switchable solids and interfaces in 

which stimuli-induced molecular-level motions can be communicated 

to the macroscopic world as changes in the 


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Reviews 

Scheme 80. Operation and truth table for a molecular half-adder based on a fluorescent molecular shuttle. [355] Note, the E!Z photoisomerizations 

reached photostationary states, shown here as percentages of the major isomer over the reaction arrows. All the fluorescence and 

absorption measurements were carried out on these photostationary state compositions and the differences in the DF and DA values were 

sufficient to discern “high” (1) and “low” (0) responses. 

properties of the material. At the very least,this requires the 

combined mechanical switching of an ensemble of molecules 

and,in the most sophisticated cases,coordinated coherent 

motions of a population of molecular machines is required. 

8.3.1. Solid-State Molecular Electronic Devices 

In a series of ground-breaking experiments that interface 

molecular-level machines with silicon-based electronics, 

molecular shuttles (Sections 4.2 and 4.3) have been employed 

as an active molecular component in solid-state molecular 

electronic devices. [440] In the first example of such devices to 

utilize interlocked molecules,a monolayer of redox-active 

degenerate two-station rotaxanes (135 4+ ,Scheme 81) was 

sandwiched between electrodes made from titanium and 


aluminum oxide. [441] The resulting junctions exhibited a 

strongly nonlinear current–voltage response at small negative 

biases. Application of an oxidizing voltage however resulted 

in an irreversible reduction in conductance. Connection of 

these fuselike switches in linear arrays created wired-logic 

gates performing OR and AND functions that displayed more 

pronounced voltage responses compared to resistor-based 

circuits,and thus demonstrating the defect-tolerance of this 

architecture for generating logic functions. 

In a second generation of devices,bistable interlocked 

molecules were employed and reversible switching achieved. 

Structures containing the tetracationic cyclophane CBPQT 4+ 

can be ordered in Langmuir films by using an amphiphilic 

counterion and the monolayers subsequently transferred onto 

solid substrates by using the LB technique. [442] The process 



Scheme 81. Chemical structure of amphiphilic [2]rotaxane 135 4+ 

employed in the first electronic switches based on an interlocked 

molecule. [441] Alignment of the molecules was achieved by exploiting 

the hydrophobic (black stoppers) and hydrophilic (light blue hydroxymethyl 

moiety) portions at the top and bottom of the molecule as 

drawn. 

was used to create a molecular switch tunnel junction (MSTJ) 

in which a monolayer of bistable [2]catenane 92 4+ 

(Scheme 54,Section 4.6.1) was sandwiched between silicon 

and titanium/aluminum electrodes. [443] These devices exhibited 

a moderate (ca. 2 ” ) increase in conductance after 

application of an oxidizing potential,while recovery of the 

initial state occurred after a reducing voltage was applied. The 

“read” voltage was in the region 0.1 to 0.3 V and did not 

interfere with the switch configuration,while the devices 

withstood many switching cycles. A rational design process 

then led to devices made from a related [2]pseudorotaxane 

(136 4+ ,Scheme 82) in which hydrophobic and hydrophilic 

regions are now directly incorporated into the molecular 

structure to allow self-organization. [444] Although larger on/off 

current ratios and absolute currents were observed,the device 

characteristics were found to vary widely between both cycles 

and devices. On further investigation,these problems were 

attributed to the formation of molecular domains,which 

means that the device characteristics were no longer determined 

by single-molecule properties. 

Further refinements of this shuttle structure produced 

amphiphilic bistable [2]rotaxanes 137 4+ and 138 4+ . Molecular 

switch tunnel junctions of these rotaxanes possessed stable 

switching voltages around 2 and + 2 V with reasonable on/ 

off ratios and switch-closed currents. [445] These favorable 

characteristics allowed preparation of nanometer-scale devices 

which displayed properties similar to the original micrometer-sized 

analogues,thus suggesting a molecular-level 

mechanism for the MSTJ operation. Furthermore,these 


Chemie 

Scheme 82. Chemical structures of amphiphilic bistable [2]pseudorotaxane 

136 4+ and [2]rotaxanes 137 4+ and 138 4+ used as the active components 

MSTJs. [444,445] Hydrophobic (black) and hydrophilic (light blue) regions are 

incorporated directly into the structures to allow self-assembly in Langmuir 

films without requiring additives. 

devices could be successfully connected to form a 2D crossbar 

circuit architecture. The circuit could be used as a reliable 64bit 

random access memory (RAM). The more demanding 

task of creating a logic circuit was also demonstrated by hardwiring 

1D circuits. A genuine 2D MSTJ-based crossbar logic 

circuit,however,will require junctions with features yet to be 

attained by using molecular systems,such as diode character 

and gain. 

A limited number of non-interlocked and nonswitchable 

control molecules (for example,a simple alkyl chain carboxylic 

acid,the free CBPQT 4+ ring,and related degenerate 

catenanes) have been tested in similar settings to provide 

supporting evidence that a molecular-level electromechanical 

mechanism is responsible for the switching observed in the 

rotaxane-based devices. [442c,443–445] The studies suggest that 

some form of bistability,together with the presence of the 

macrocycle,are necessary for the switching properties and are 

therefore consistent with a mechanism whereby electronically 

stimulated shuttling alters the junction conductance. However,devices 

made from a single station [2]rotaxane still 

exhibit conductance switching,albeit with a significantly 


147

Reviews 

lower on/off ratio than the two-station analogues 137 4+ and 

138 4+ . [444] Crucially,all the solid-state devices exhibit marked 

temperature dependence,which showed that at least one 

thermally activated step is involved in their operation. This is 

in line with the observation of a metastable state for shuttling 

in solution at low temperature (Section 4.3.4), [228f] as well in 

similar interlocked systems aligned in SAMs, [410] Langmuir 

films,and Langmuir–Blodgett monolayers (Section 8.1), [411] 

and dispersed in a solid-state polymer electrolyte (Section 

8.3.2). [446] By comparison of these systems,together 

with the performance of a different rotaxane analogue in 

solution,in a polymer electrolyte,and in MSTJs, [228i] it has 

been demonstrated that the ground-state thermodynamics of 

these shuttles are controllable by manipulation of chemical 

structure and are qualitatively independent of the surrounding 

medium. However,the nature of the environment does 

strongly affect the kinetics for relaxation of the non-equilibrium 

state as one would expect,and the experimentally 

determined values from each environment quantitatively 

support a common molecular-level switching mechanism 

based on shuttling motion. [191ad,228f,i] The proposed mechanism 

for operation of the solid-state electronic devices is summarized 

in Figure 45. 

Identification of the high conductance state as that with 

the cyclophane encircling DNP (state (d),Figure 45) is 

supported by quantum mechanical computational studies in 

which the I–V response was simulated for a model pseudo- 

Figure 45. Proposed mechanism for the operation of rotaxane-based MSTJs. [191x,y,ad,228f] The coloring of 

functional units corresponds to that used for structural diagrams in Scheme 82. a) In the ground state, the 

tetracationic cyclophane (dark blue) mainly encircles the TTF station (green) and the junction exhibits low 

conductance (the precise ratio of co-conformers in this state is dependent on the exact chemical structure 

of the [2]rotaxane and in some cases can also be temperature dependent). b) Application of a positive bias 

results in one- or two-electron oxidation of the TTF units (green!pink) and the resulting electrostatic 

repulsion causes shuttling of the ring onto the DNP station (red, c). d) Returning the bias to near 0 V 

reveals a high conductance state in which the TTF units have been returned to neutral, but translocation of 

the cyclophane has not yet occurred, because of a significant activation barrier. Thermally activated decay 

of this metastable state ((d)!(a)) may occur slowly, over time (dependant on temperature) or can be 

triggered by application of a negative voltage (e) which temporarily reduces the cyclophane to its diradiacal 

dication form (dark blue!orange), thus allowing facile recovery of the thermodynamically favored coconformation 

(f). A similar mechanism is applicable in the operation of devices based on analogous 

[2]catenanes. 


rotaxane in each of the two co-conformations (that is, 

corresponding to (a) and (d) in Figure 45). [447] The picture 

presented in Figure 45 is not entirely accurate,however, 

particularly with regard to the conformation of the rotaxane 

molecules. Analysis of the structures of Langmuir and LB 

films composed of various amphiphilic [2]rotaxanes indicates 

that unless high surface pressures or larger hydrophilic 

stoppers are employed,a very acute angle to the interface is 

adopted,probably as a result of the hydrophilicity of the 

tetracationic cyclophane. [448] These experimental results were 

recently reproduced by a molecular dynamics study of the 

Langmuir films,in which similar tilted arrangements were 

observed for both co-conformations. [449] The overall conformation 

of the thread portion is folded and dependent on the 

position of the macrocycle. Folded conformations resulting 

from “alongside” interactions between the CBPQT 4+ moiety 

and the vacant p-donor station are often observed in 

solution, [191ad, 217j,225e,228c,d,h,238] so it seems likely that such 

arrangements are also present at surfaces and in the solid 

state. The importance of conformation on electronic properties 

was highlighted in a computational study in which density 

functional theory was used to calculate the electronic 

structure of various functional components of the rotaxanes 

and from which a description of the rotaxane frontier 

molecular orbitals could be derived. [450] It was found that 

the ring-on-DNP co-conformation was only the most conductive 

if the cyclophane participates directly in electron 

tunneling by providing low-lying 

LUMO orbitals. Such a situation is 

most plausible for a folded conformation 

with direct interactions between 

the ring and the unoccupied station. 

The molecular dynamics simulation of 

Langmuir films, [449] as well as a similar 

treatment of thiol-anchored SAMs on 

Au(111), [451] suggest that such folded 

conformations form thermodynamically 

favored superstructures,while 

the added intra- and intermolecular 

interactions do not alter the relative 

stabilities of the two co-conformations. 

Such arrangements actually place the 

rotaxane functional units in relative 

orientations comparable to the analogous 

[2]catenane which originally displayed 

very similar device character- 

istics. Density functional calculations 

for optimized monolayers of [2]catenane 

92 4+ sandwiched between two 

gold electrodes demonstrated again 

that the ring-on-DNP co-conformation 

exhibits the higher conductance at 

small applied read bias,with the conduction 

involving HOMOs from TTF 

as well as DNP and LUMOs from 

CBPQT 4+ . [452] 

Clearly the most convincing verification 

of an electromechanical mechanism 

for conductance switching 



would be direct real-time observation of the shuttles in an 

operating solid-state device. Probing a single molecular 

monolayer confined between two electrodes is a challenge 

which cannot yet be routinely met by modern-day analytical 

methods,and preliminary attempts at using grazing-angle 

refection-absorption infrared spectroscopy (RAIRS) to study 

mechanical movements in such scenarios have proven unsuccessful. 

[453] Following on from indirectly observed shuttling in 

Langmuir monolayers [411] (see Section 8.1),the first direct 

evidence for shuttling in such a condensed phase was recently 

obtained by using X-ray reflectometry. [454] These results have 

also confirmed the considerably tilted and folded rotaxane 

conformations which were previously inferred (see above). 

Although these devices show potential as possible components 

for genuine single-molecule electromechanical 

switches,a significant barrier to achieving this goal is the 

nature of the physical connections used to wire the device. At 

very small dimensions,it is expected that metal wires will 

exhibit the best conductance characteristics,but unfortunately 

a range of molecular shuttle devices with two metal 

electrodes failed to demonstrate switching properties that 

were dependent on the nature of the organic monolayer. [455] 

Indeed,the polarity of molecule–metal interfaces and the 

potential for the formation of metal filaments within molecular 

monolayers are emerging as recurring issues in metalcontacted 

organic molecular electronics. [456] However,catenane-based 

MSTJs which utilize single-walled carbon nanotubes 

in place of the silicon electrode have been successfully 

created and this may provide a valuable alternative in the 

creation of real-world devices. [457] Whether the philosophy of 

using thermally activated nuclear motions which occur on 

timescales many orders of magnitude slower than electron 

motions is the right one for a practical molecular computer or 

not is not necessarily the most valuable aspect of this work. 

The interfacing of molecular machines with electronics opens 

up the possibility of many types of practical hybrid devices 

and will doubtless prove seminal in getting molecular motors 

and machines out of solutions in laboratories and into 

technological devices. 

8.3.2. Using Mechanical Switches to Affect the Optical Properties 

of Materials 

The configurational changes that occur in photochromic 

dopants have been used for a number of years to initiate 

changes in a number of liquid-crystal properties. [458] The 

trans!cis photoisomerization of stilbene or azobenzene 

dopants,for example,can cause reversible disruption of the 

nematic mesophase,effectively “turning off” liquid crystallinity. 

However,a more subtle form of mechanical molecularlevel 

control is achievable in systems where the mesophase 

structure is maintained throughout. It is possible to orient 

photochromic dopants in a liquid-crystalline phase through 

axis-selective photoconversion by applying plane-polarized 

light to stimulate repeated photoisomerization. This directional 

orientation triggers alignment of the whole liquidcrystal 

phase. A second vector of polarization can then be 

used to produce a differently aligned state. This type of 

process has recently been modeled as a Brownian ratchet— 


Chemie 

each of the interconverting forms of the dopant molecule 

move over a different potential energy surface as a result of 

different interactions with the liquid-crystalline phase,while 

transitions between them are fueled by the optical stimulus. 

[459] Such systems clearly exhibit remarkable amplification 

of a relatively small photoinduced configurational change 

which causes a global orientation change in the bulk. It is even 

possible to create surface-controlled systems where a monolayer 

of photochromic species (a so-called “command surface”) 

controls the alignment of a whole liquid-crystal layer in 

contact with it. Potential applications of this photoinduced 

mechanical molecular-level motion include optical recording 

media and light-addressable displays. [458] 

Chiral dopants can induce the formation of chiral nematic 

(cholesteric) phases. If the dopants contain photoswitchable 

units,variations in the expression of chirality can be achieved. 

Recently a dopant of fixed chirality bound to an azobenzene 

photoswitch was used to reverse the screw sense of the 

cholestric phase. [460] Some chiroptical switches,such as the 

overcrowded alkenes discussed in Section 2.2,have a change 

in helicity associated with their photochromic switching and 

so are well-suited to switching the cholesteric liquid-crystal 

chirality. [461] Unidirectional molecular motor 46 (Figure 18, 

Section 2.2) has also been shown to play such a role. [462] Of the 

three isomers which can be isolated at room temperature, 

each exerts a different helical twisting power on the liquidcrystalline 

matrix,with opposite dopant helical handedness 

inducing contrary screw senses in the liquid crystal. Photochemical 

and thermal unidirectional rotation of the motor 

was shown to occur within the liquid-crystal matrix,albeit 

with reduced efficiency and rates compared to solution 

studies. Liquid-crystal films doped with (P,P)-trans-46 gave 

a cholesteric phase with right-handed helicity and displayed a 

violet color. Photoirradiation (l > 280 nm) at room temperature 

leads to a decrease in the proportion of this isomer and 

concomitant increases in the amount of (P,P)-cis-46 (which 

has a much weaker right-handed helical-twisting power) and 

(M,M)-trans-46 (which exerts a left-handed helical twist). The 

combined effect of the change in dopant isomer composition 

is to progressively change the color of reflected light from 

violet through to red (Figure 46). A blue shift of the reflected 

wavelength could also be achieved on heating the film to 

608C which converts any (M,M)-trans-46 present back into 

(P,P)-trans-46. [462] As a consequence of the induced helicity in 

the liquid-crystal phase,it seems likely that the reorganizational 

motions triggered by isomerization of the dopant 

molecule are directional in nature. The color change, 

however,is not a result of the unidirectional trajectory of 

the motor; rather it is an expression of the system s state at 

Figure 46. Color changes in a liquid-crystal film doped with 46 

(6.16 wt%). [462] Starting from 100% (P,P)-trans-46, the sample is 

irradiated with light of l > 280 nm at room temperature. The pictures 

of the film shown from left to right were taken at 0, 10, 20, 30, 40, and 

80 s. Reprinted with permission from Ref. [462]. 


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Reviews 

any particular moment in time,a function of the 

different populations of a three- (or four-) state 

switch (see also Section 8.3.3). In other words,in this 

situation the motor molecule is simply acting as a 

switch and the directionality of the rotation of its 

components probably plays no role in changing the 

liquid-crystal color. 

The use of controlled molecular motion in 

polymer films to generate patterns visible to the 

naked eye (Figure 47) has been demonstrated with a 

Figure 47. Images obtained by casting films of polymer 139 on quartz 

slides, covering them with an aluminum mask, and exposing the 

unmasked area to dimethyl sulfoxide vapors for 5 min. [463] The photographs 

were taken while illuminating the slides with UV light (254– 

350 nm). The symbols of Sony Playstation are illustrative of the types 

of patterns that can be created. 

molecular shuttle based fluorescent switch derivatized 

with poly(methyl methacrylate) (139, 

Scheme 83). [463] A polymer film INHIBIT logic gate 

based on a combination of stimuli-controlled submolecular 

positioning of the ring and protonation 

was also demonstrated (140/140·2 H + ,Scheme 83, 

Figure 48). [463] 

Scheme 83. Polymeric environment-switchable molecular shuttles 139 

and 140/140·2H + . [463] 


Figure 48. A molecular-shuttle Boolean logic gate that functions in a polymer 

film. [463] a) The aluminum grid used in the experiment. The coin shown for scale 

is a UK 5p piece. b) The pattern generated when films of 140 were exposed to 

trifluoroacetic acid vapor for 5 min through the aluminum grid mask. c) The 

criss-cross pattern obtained by rotating the aluminum grid 908 and exposing the 

film shown in (b) to DMSO vapor for a further 5 min. Only regions exposed to 

trifluoroacetic acid but not to DMSO are quenched. The truth table for an 

INHIBIT logic gate is shown in the inset. The photographs of the slides were 

taken in the dark while illuminating with UV light (254–350 nm). 

Many of the switchable rotaxane and catenane systems 

which employ charge-transfer interactions between the components 

intrinsically involve changes in absorption profiles— 

and therefore color—concomitant with shuttling. Incorporation 

of a rotaxane similar to 124 4+ (Scheme 73) into a solidstate 

polymer electrolyte gives an electrochromic device in 

which a color change occurs on application of an oxidizing 

potential. [446] The observed color change is consistent with 

that seen on shuttling in solution for this family of catenanes 

and rotaxanes (for example,[2]catenane 92 4+ ,Scheme 54, 

Section 4.6.1),while on subsequent reduction,the reverse 

color change occurs slowly,and is indicative of the slow 

relaxation of the non-equilibrium system in the solid state. 

Both these observations serve as strong evidence for shuttling 

in the condensed phase (as discussed in Section 8.3.1). 

Stoddart,Goddard,and co-workers have recently proposed 

an extension of this concept,based on [2]catenane 92 4+ ,but 

incorporating a third,intermediate and electroactive,station 

to create a three-state switchable catenane in which each of 

the states should be characterized by a different color arising 

from the intercomponent charge-transfer interactions. [464] 

8.3.3. Using Mechanical Switches To Affect the Mechanical 

Properties of Materials 

Materials which can transduce an external stimulus into a 

mechanical response are at present probably best exemplified 

by piezoelectrics,but the development of molecular materials 



which exhibit similar—or potentially even more sophisticated—properties 

is an area of intense interest. [465] It is well 

established that conformational changes in polymers can 

result in mechanical changes at the macroscopic level. Such 

effects have been extensively studied for over half a century in 

stimuli-responsive hydrogels. These water-swollen 3D-crosslinked 

networks of neutral or ionic (also known as polyelectrolytes 

in this case) amphiphilic polymers can undergo 

reversible phase transitions in response to a number of 

stimuli,including pH,temperature,solvent composition, 

electric fields,and light. The phase changes result from 

altering the balance between hydrophilic and hydrophobic 

forces and can be accompanied by volume changes of up to 

two orders of magnitude. [466] These were perhaps the first 

synthetic chemomechanical systems to be investigated and 

their significance was recognized early on by Katchalsky and 

co-workers,who developed a number of remarkable macroscopic 

devices for directly and continuously transducing 

chemical potential into mechanical work. [467,468] Recent developments 

include using photons to induce phase transitions, [469] 

the use of oscillating chemical reactions to control the 

environment for pH-responsive gels to produce autonomously 

fluctuating chemomechanical systems, [470] and “core– 

shell” architectures to give materials with multistep volume 

changes. [471] Synthesis and optimization of such systems in the 

future may also be expedited by a supramolecular approach 

to their construction. [472] A wide range of technologically 

relevant devices have been proposed and are under development 

using such materials,with functions including the 

binding and release of guests, [473] flow control valves for 

microfluidic devices, [474] a macroscopic walking device, [475] 

control of enzyme activity, [476] as well as a number of 

biomedical applications. [477] Incorporation of molecular recognition 

units into the gel network can lead to volume 

changes—and,in turn,other effects—upon binding of a 

specific guest molecule or ion. [478] This approach has not only 

been successful for relatively simple host–guest systems,but 

with redox-active enzymes,such as glucose oxidase. Binding 

to,and subsequent oxidation of,the substrate produces the 

charged form of the enzyme cofactor which initiates the gel 

phase transition. [478c,d] 

Another emerging area of molecular-level mechanical 

motion in which hydrogels and other responsive polymeric 

materials have been applied,is the development of shapememory 

materials,in particular ones which are biologically 

compatible. [479] While most systems use a temperature change 

to induce recovery of the “memorized” shape,light-induced 

shape-memory effects have recently been reported in which a 

photoinitiated radical reaction has been used to rearrange 

covalent cross-links [480] or the reversible formation of crosslinks 

through a [2+2] cycloaddition which can be induced and 

reversed by irradiation with light of different wavelengths. [481] 

Stimuli-induced mechanical changes can also be induced 

in conducting polymers. Electrochemical oxidation and 

reduction of polypyrrole,polythiophene,or polyaniline films 

induces counterion transport into or out of the polymer 

matrix,thus resulting in volume changes. [482] Such effects were 

first demonstrated for macroscopic devices immersed in 

aqueous electrolytes,but the long reaction times and the 


Chemie 

small forces generated are practical limitations of such 

systems. More recently,solid-state, [483] gel, [484] and ionicliquid 

[485] electrolytes have been employed,while the development 

of microfabricated devices has been successful in 

realizing quite complex and potentially technologically relevant 

electrochemomechanical actuators. [482c] The combination 

of the conducting polymer technology with a hydrogel 

material has been used to overcome some of the problems 

associated with each individual approach to demonstrate a 

novel drug-delivery system, [486] while similar processes are 

now being investigated in conductive supramolecular crystalline 

materials. [487] A related but novel mechanism for electromechanical 

actuation,which avoids many of the drawbacks 

associated with redox-induced dopant diffusion,has been 

realized in sheets of entangled nanotube bundles [488] and in 

porous films of gold nanoparticles. [489] The process (termed 

double-layer charging) does not involve any redox reaction, 

but rather the injection of charge into these high surface area 

materials attracts electrolyte ions to the surfaces,thus 

resulting in surface-stress-induced deformation. 

In the preceding examples a macroscopic mechanical 

change is produced by the combined effect of a number of 

nonspecific conformational changes in the polymeric network. 

Even if in some cases this is the result of a specific 

recognition event,the mechanical change is not an intrinsic 

feature of the molecular components. There are a number of 

systems,however,in which particular submolecular conformational,co-conformational,and/or 

configurational switches 

can be used to directly trigger macroscopic motion. These 

approaches circumvent the problems of diffusion-limited 

rates and uniformity of response throughout the material. 

The incorporation of configurational switches,especially 

azobenzenes,to reversibly control secondary and tertiary 

structure in biopolymers and synthetic oligomers (Section 

2.2) or to control long-range order in liquid-crystalline 

phases (Section 8.3.2) has already been discussed. A similar 

approach can be used for synthetic polymers,where the effect 

is often a macroscopically detectable response. 

Several types of azobenzene-containing polymer films 

undergo contraction–extension cycles on photoisomerization, 

[490] while other physical properties such as viscosity and 

solubility can be similarly controlled. [491] Length changes in an 

azobenzene-containing polymer have recently been observed 

at the single-molecule level using AFM. [492] One end of a 

polyazopeptide (a polymer of azobenzene units linked by 

dipeptide spacers) was isolated on a glass slide while the other 

was attached to a gold-coated AFM tip through a thioether– 

gold bond (Scheme 84). At zero applied force,the polymer 

showed repeated shortening and lengthening on photoisomerization 

of the azobenzene units to cis and trans,respectively. 

Furthermore,this experimental arrangement was used to 

demonstrate the transduction of light energy into mechanical 

work. A “load” was applied to one of the polyazopeptides—in 

its fully trans form—by increasing the force applied by the 

AFM tip from 80 pN to 200 pN,thus resulting in a stretching 

of the polymer. Photoisomerization to increase the percentage 

of cis linkages in the polymer strand resulted in 

contraction,even against the externally applied force (“raising 

the load”). Removal of the “load” (reducing the applied 


151

Reviews 

Scheme 84. Experimental set-up for the observation of single-molecule extension and 

contraction using AFM (the azobenzene unit is shown as the extended Z isomer). [492] 

force) followed by reisomerization to the trans form,restored 

the polymer to its original length,ready to lift another load. 

The work done in this way by the single-molecule optomechanical 

device was approximately 5 ” 10 20 J. 

Analogous to controlling the chirality of liquid-crystal 

phases,and following the observation of environment-sensitive 

screw-sense inversion in certain biopolymers,there is 

considerable interest in remotely controlling the handedness 

of synthetic helical polymer systems. [493] While this has been 

achieved in a number of nonspecific ways (for example,by 

changing the solvent or temperature) molecular switches can 

also be employed. Chiral azobenzene side chains permit 

reversible switching between P and M helices by controlling 

the proximity of the chiral center to the polymer backbone. 

[494] Circularly polarized light has been used to generate 

an enantiomeric excess in an axially chiral alkene pendant 

group. [495] As observed for the liquid-crystal examples,even a 

very small enantiomeric excess is amplified into a bulk chiral 

rearrangement of the polymer. Thin films of liquid-crystalline 

or amorphous azobenzene side-chain polymers can also be 

reoriented on the nanoscale level with linearly polarized 

light. [496] The photoinduced anisotropy confers dichroism and 

birefringence on the material,thus suggesting potential for 

application in holographic data storage. [497] Intriguingly,such 

optically induced birefringence gratings are created in a 

process which can also involve mass transport to give surface 

relief features detectable by AFM or even the naked 

eye. [498,499] Indeed,the properties of liquid crystals and 

polymers can be combined in liquid–crystal elastomers— 

polymers constructed from mesogenic monomers which can 

become oriented in an ordered manner. The nematic to 

isotropic phase transition can result in a macroscopic 

response. [500] If an azobenzene configurational switch is also 

incorporated,switching between nematic and isotropic 

phases,or reorientation of the chromophores,can be achieved 

on irradiation with linearly polarized light,and quite specific 

changes in the elastomer film can be induced. [501] This has 

even been demonstrated in a system where the azobenzene 

photoswitch is not covalently attached to the main polymer 

backbone and,in this case,the light-triggered deformation 

can also propel the elastomer across a water surface. [501g,502] 

On doping a nonpolymeric liquid-crystal film with lightdriven 

unidirectional rotor 141 (Figure 49 a,a member of the 

“third generation” series discussed in Section 2.2),the helical 

organization induced by the dopant results in a fingerprintlike 

structure to the surface of the film. [503] Both thermal 


relaxation steps can occur at room temperature 

with this motor molecule. Irradiation of the film 

with light alters the distribution of the isomers 

present and,as they have different helical twisting 

powers,the organization of the liquid crystal is 

changed. This results in a rotational reorganizaton 

of the surface structure,which can be followed by a 

glass rod sitting on the film (Figure 49b). After 

irradiation of the sample for ten minutes,however, 

the rod s rotary motion ceases,which is indicative 

of the photostationary state being reached. 

Although there continues to be a directional flux 

Figure 49. a) Chemical structure of light-driven unidirectional molecular 

rotor 141. [503] b) Rotation of a glass rod (5 ” 28 mm) on a liquidcrystal 

film doped with 141 (1 wt%). Pictures (from left to right) were 

taken at 0, 15, 30, and 45 s and show clockwise rotations of 0, 28, 141, 

and 2268, respectively. Scale bars: 50 mm. The pictures are reprinted 

with permission from Ref. [503]. 

of motor molecules between the different isomers,the net 

distribution of the isomers is no longer changing (see 

Section 2.2) and so the reorganization of the liquid-crystal 

matrix ceases. Removing the light stimulus allows the 

population of the “unstable” isomer to decay,returning the 

system to its starting state,accompanied by rotation of the rod 

in the opposite direction. Similar to the color switching 

discussed in Section 8.3.2 (Figure 46),this effect is not a 

product of the directional trajectory of a motor. The liquidcrystal 

organization reflects the distribution of dopant 

isomers at any particular moment in time,while the directionality 

of the rod s movement is due to the original chirality 

of the liquid-crystalline phase and dopant. 

In terms of conducting polymers,it is possible that an 

intrinsic molecular-level change of length is a contributing 

factor to the mechanism of operation of polyaniline-based 

electrochemomechanical actuators. [504] However,new systems 

are being developed in which a designed molecular-level 

conformational change is responsible for inducing mechanical 

motion. These include a thiophene-fused [8]annulene which 

switches between puckered and planar forms depending on 

the oxidation state. [505] The conformational flexibility of 

calix[4]arenes has led them to be incorporated as hinge 

elements into conducting polymers based on oligothiophenes. 

[506] It has been proposed that electrochemical switching 

of p–p interactions between adjacent oligothiophene units 



should lead to microscopic and macroscopic mechanical 

motions,although there is some debate over the precise 

mechanism. [507] 

Although the metal-templated rotaxane dimer illustrated 

in Figure 41 (Section 8.2.2) exhibits reversible switching of its 

molecular length,cooperative coherent motion in a population 

of 130 2 to generate a macroscopic response has yet to be 

achieved. The first demonstration of macroscopic mechanical 

motion triggered by shuttling in a rotaxane was recently 

demonstrated using electroactive [3]rotaxane 142 8+ . [508] Oxidation 

of the TTF stations (green!pink) results in shuttling 

of the cyclophanes onto the hydroxynaphthalene units (red), 

significantly shortening the inter-ring separation (Scheme 85). 

A self-assembled monolayer of 142 8+ was deposited on an 

array of microcantilever beams which had been coated on one 

side with a gold film and the set-up then inserted in a fluid 

cell. The chemical oxidant Fe(ClO 4) 3 was added to the 

solution and the combined effect of co-conformational 

change in approximately six billion randomly oriented 

rotaxanes on each cantilever was an upward bending of the 

beam by about 35 nm. Reduction with ascorbic acid returned 

the cantilever to its starting position. The process could be 

repeated over several cycles,albeit with gradually decreasing 

amplitude. [509] 

8.3.4. Using Mechanical Switches To Affect Interfacial Properties 

The surface properties of an object are crucial in 

determining many aspects of its behavior and the ability to 

remotely change these characteristics could have a significantly 

impact on both current and future technologies. Many 

of the stimuli-switchable surfaces developed to date rely on 

induced submolecular motions to bring about the change in 

properties. [510] 

Anchoring stimuli-responsive polymers to solid substrates 

has allowed the creation of switchable surfaces based on 

Scheme 85. Chemical structure of [3]rotaxane 142 8+ and schematic representation of its operation as a molecular actuator. [508] 


Chemie 


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Reviews 

environmentally responsive 

hydrogel polymers and 

polyelectrolytes,photoresponsiveazobenzene-containing 

polymers,and dendritic 

polymers,as well as 

changes arising from microphase 

segregation mechanisms 

for block-copolymer 

and mixed polymer brushes. 

These approaches have 

been extensively reviewed 

elsewhere, [510,511] and can 

give rise to switchable surface 

patterning,wettability, 

adhesion,and control of 

other interfacial interactions. 

Integration of these 

functional organic structures 

with inorganic and 

biomaterials is an important 

current goal,particularly 

with a view to potential 

applications. [511d] For example,the 

intercalation of Au 

nanoparticles into an electrode-mountedsolventresponsive 

polymer gel 

allowed control of the interfacial 

conductivity through 

variation in the separation 

of the nanoparticles. [512] The 

encapsulation of a thermally 

responsive polymer in a porous inorganic matrix 

resulted in a switchable molecular filter, [513,514] while a 

covalently tethered monolayer of the same polymer has 

been used to reversibly adsorb proteins in an integrated 

microfluidics chip. [515] 

The direct deposition of bistable small molecules onto 

solid substrates as thin films can also result in interesting 

switching phenomena which amplify the molecular-level 

motion to give a large response. On polar surfaces such as 

mica,monolayer films of amphiphilic benzylic amide [2]catenane 

91 (Scheme 53) prefer to adopt co-conformation alkyl- 

91,irrespective of the nature of the depositing solution. [516] 

Continued deposition from acetone results in stacked monomolecular 

terraces that are clearly observable by AFM. 

Further deposition from chloroform,however,results in the 

incoming molecules (adopting the amido-91 form in the 

apolar environment) inducing a co-conformational change in 

the film so that amido-91 is adopted by all the molecules,thus 

minimizing the packing energy. The result is a completely 

different morphology: decreased interaction with the substrate 

causes complete rupture of the film to give stacks 

several tens of nanometers in height. 

A rotaxane-based molecular shuttle has been attached to 

mesoporous silica particles and used to control access to pores 

in the material (Figure 50)—a reversible analogue of an 

earlier pseudorotaxane-based design (Section 8.1). [517] When 


Figure 50. a) Chemical structure of a bistable [2]rotaxane (143 4+ ) used to create a reversible molecular 

valve. [517] b) Schematic representation of the operating cycle for a reversible molecular valve. Colors not 

defined in (a) are: pink = TTF + ; light blue = guest molecules. 

the CBPQT 4+ ring sits on the preferred TTF station,access to 

the interior of the nanoparticles is unrestricted and diffusion 

of solutes from the surrounding solution can occur. Chemically 

induced oxidation of the TTF unit results in a shuttling 

of the ring closer to the solid surface,thereby blocking access 

to the pores and trapping any solute molecules inside. 

Reduction of the TTF unit reverses the mechanical motion, 

thus releasing the guest molecules and returning the system to 

its initial state. 

A potentially useful way of detecting and subsequently 

communicating the state of any type of molecular switch is to 

translate its state into an electrical signal. [97s,403e,518] This has 

been accomplished for a molecular shuttle attached through 

one end of the thread to the surface of a gold electrode. [519] 

Photochemically induced shuttling of a cyclodextrin ring 

closer to the electrode surface was detectable as an increase in 

the rate of electron transfer on oxidation of a redox-active 

ferrocene unit attached to the mobile ring. Shuttling has also 

been invoked to explain the operation of a remarkable device, 

in which a rotaxane connects the redox-active enzyme glucose 

oxidase to an electrode surface. [520] When the device is 

constructed without the rotaxane macrocycle (a CBPQT 4+ 

cyclophane) no electronic communication between the redox 

enzyme and the electrode is detected. With the rotaxane 

linker,however,bioelectrocatalyzed oxidation of glucose 

occurs. It is proposed that the cyclophane acts as a two- 



electron relay,that is,acting as an intermediate for electron 

transfer between the enzyme and the electrode. It is likely 

that this role involves movement of the reduced ring towards 

the electrode as reduction destroys its charge-transfer interactions 

with the thread. Such a mechanism may also be at play 

in an earlier,fully synthetic,system where the ring acts as a 

relay between a photoelectroactive CdS nanoparticle and the 

electrode. [521] In a structurally simpler synthetic system 

(Scheme 86),electrochemically induced shuttling has been 

directly proven and shown to switch a number of properties of 

the functionalized electrode. [522] The cyclophane can be 

reversibly reduced and oxidized by applying appropriate 

potentials at the electrode. Chronoampometry demonstrates 

that the reductive electron transfer is significantly slower than 

the oxidation,thus indicating a shorter electrode–macrocycle 

separation in the reduced state. Positional integrity of the 

macrocycle in both states was quantitative to the limits of 

detection,however,fast two-potential-step chronoampometry 

experiments allowed a detailed study of the kinetics for 

shuttling (k 1 and k 2 in Scheme 86) in each direction at various 

temperatures and in solvent systems of differing viscosity. [522b] 

Impedance spectroscopy indicated a difference in the doublecharge-layer 

capacitance in the two states,while the decrease 

of the cyclophane charge and shuttling to reveal the alkyl 

chain-based thread also increases the hydrophobicity of the 

electrode surface. This was demonstrated by a change in the 

contact angles for an electrolyte droplet placed on the 

electrode. [522a] 

Inspired by a number of natural phenomena,the design of 

surfaces with special—and in particular switchable—wettability 

characteristics has attracted much interest in recent 

years. [523] Monolayers of various photochromic switches have 

been used to control the wettability of a surface. [510] In line 


Chemie 

with an earlier computational study, [524] variation of an 

electrostatic potential has been used to alter the conformation 

of a SAM of long-chain alkanethiols terminated with 

carboxylate groups and thus affect the surface hydrophobicity. 

[525] Applying a negative potential to the gold surface repels 

the carboxylate groups,which causes the chains to “stand up” 

and thus endows a strongly hydrophilic character to the 

surface; a positive Au potential attracts the carboxylate 

groups,which causes folding that exposes the hydrophobic 

alkyl chains at the surface. A low-density SAM must be 

utilized to allow significant conformational freedom. Similar 

switchable surface-wettability properties were also demonstrated 

by using positively charged bipyridinium end groups 

instead of the negatively charged carboxylate groups. [526] 

More recently,a carboxylate-terminated low-density SAM 

was manufactured by self-assembling cyclodextrin pseudorotaxanes 

on a gold surface before washing off the spacefilling 

macrocycles with a polar solvent. [527] The resulting 

surface demonstrated conformational switching and could be 

used to reversibly adsorb both a cationic and a near-neutral 

protein at the interface. 

A dramatic illustration of the power of controlled 

molecular-level motion is the use of conformationally switchable 

monolayers to control macroscopic liquid transport 

across surfaces. It has been shown both theoretically [528] and 

experimentally [529] that a liquid droplet on a surface with 

spatially inhomogeneous surface free energy will tend to 

move in the direction of the higher surface free energy. [530,531] 

Surface motions of droplets have been controlled by wettability 

gradients and steps in a number of different 

ways, [529,530,532,533] yet it remains a particular challenge to 

endow a surface with remotely controllable surface free 

energy so as to generate macroscopic motion of a droplet 

Scheme 86. Electrochemically induced shuttling on an electrode surface. [522] The submolecular co-conformational motion is transduced into an 

electronic signal in terms of a change in the electron-transfer kinetics and also results in a change in the capacitance and hydrophobicity of the 

monolayer. The rate constants shown for the shuttling steps (k 1 and k 2) are those measured at 258C in pure water. Only k 2 was found to vary with 

temperature, while both rates decreased with increasing solvent viscosity. 


155

Reviews 

along any path. [534] As well as addressing a number of 

fundamental scientific issues,such a system would undoubtedly 

be of major value in the emerging fields of microfluidics 

and lab-on-a-chip technologies which currently rely on 

potentially damaging strong electric fields,air bubbles,or 

expensive microscopic pumps to transport small quantities of 

liquids. [535] 

A monolayer of azobenzene-substituted calix[4]arene 144 

(Scheme 87) provides a photoresponsive surface on which the 

Scheme 87. Molecular structure of the azobenzene unit used to create 

a photoresponsive surface for the control of liquid motion. [536] The 

macrocyclic calix[4]arene scaffold ensures sufficient free volume to 

allow full configurational motion of the azobenzene moieties, even in a 

tightly packed monolayer. 

motion of liquid droplets could be controlled simply by 

irradiation with light. [536] A droplet of olive oil on the all-cis 

surface was irradiated at 436 nm with an asymmetrical 

intensity so that more isomerization to the trans form 

occurred on one side of the droplet compared to the other. 

The resulting gradient in the surface free energy caused the 

droplet to move away from the trans-rich region. This motion 

could be continued by “chasing” the droplet with the light,or 

else by resetting the surface at the front of the drop to a cisrich 

state with a spatially controlled irradiation at 365 nm, 

followed by a further cycle of 436 nm towards the rear and so 

on,with the motion carried out in a stepwise fashion. The 

potential utility of this approach was demonstrated in a 

number of ways: a liquid droplet could be used to move a 

millimeter-sized glass bead across the surface; the same 

approach could be used to functionalize a capillary tube and 

move liquids along it; and finally,an organic chemical 

reaction could be performed by bringing two droplets 

together,each containing one of the reactants. [536] 

Recently,a similar effect was demonstrated using a 

photoresponsive surface based on molecular shuttles. [537] 

The millimeter-scale directional transport of diiodomethane 

drops across a surface (Figure 51) was achieved using the 

biased Brownian motion of the components of stimuliresponsive 

rotaxane 145 (Scheme 88) to expose or conceal 

fluoroalkane residues and thereby modify the surface tension. 


Figure 51. Lateral photographs of light-driven directional transport of a 

1.25 mL drop of diiodomethane across the surface of an (E)-145·11- 

MUA·Au(111) substrate on mica arranged flat (a)–(d) and up a 128 

incline (e)–(h). [537] a) Before irradiation (pristine (E)-145). b) After 

215 s of irradiation (20 s prior to transport) with UV light in the 

position shown (the right edge of the droplet and the adjacent 

surface). c) After 370 s of irradiation (just after transport). d) After 

580 s of irradiation (at the photostationary state). e) Before irradiation 

(pristine (E)-145). f) After 160 s of irradiation (just prior to transport) 

with UV light in the position shown (the right edge of the droplet and 

the adjacent surface). g) After 245 s of irradiation (just after transport). 

h) After 640 s irradiation (at the photostationary state). For clarity, a 

yellow line is used on photographs (f)–(h) to indicate the surface of 

the substrate. 

Scheme 88. Stimuli-induced positional change of the macrocycle in 

the fluorinated molecular shuttle 145·2H + . [537] 



The collective operation of a monolayer of the molecular 

shuttles attached to a SAM of 11-mercaptoundecanoic acid 

(11-MUA) on Au(111) (Figure 52) was sufficient to power the 

movement of the microlitre droplet up a twelve degree incline 

Figure 52. A photoresponsive surface based on switchable fluorinated 

molecular shuttles. [537] Light-switchable rotaxanes with the fluoroalkane 

region (orange) exposed ((E)-145) were physisorbed onto a selfassembled 

monolayer of 11-MUA on Au(111) deposited onto either 

glass or mica to create a polarophobic surface, (E)-145·11-MUA·Au- 

(111). Illumination with light of wavelength 240–400 nm isomerizes 

some of the E olefins to Z causing a nanometer displacement of the 

rotaxane threads in the Z shuttles which encapsulate the fluoroalkane 

units, thus leaving a more polarophilic surface, (E)/(Z)-145·11- 

MUA·Au(111). The contact angles of droplets of a wide range of 

liquids change in response to the isomerization process. 

(Figure 51 e–h). In doing this,the molecular machines effectively 

employ the energy of the isomerizing photon to do 

work on the drop against gravity. In this experiment, 

approximately 50 % of the light energy absorbed by the 

rotaxanes was used to overcome the effect of gravity,with the 

work done stored as potential energy (the raised position of 

the droplet up the incline). 

The above examples demonstrate quite extraordinary 

application of collective submolecular motions to alter the 

macroscopic properties of a surface and in turn induce 

movement of a macroscopic object. [538] However,the changes 

in the surface free energy involved are relatively small. It is 

well known that surface roughness can amplify both hydrophobicity 

and hydrophilicity. [523] A micropatterned surface 

functionalized with a solvent-sensitive mixed polymer brush 

could switch between a hydrophilic and a superhydrophobic 

state. [539] Reversible switching between superhydrophobicity 

and superhydrophilicity has been achieved on a static micropatterned 

surface, [540] as well as on a dynamic nanostructured 

surface, [541] in both cases covered with a temperature-responsive 

polymer. A similar approach has been used to amplify the 

light-induced wettability switching for a spiropyran-functionalized 

surface. [542] As well as increasing the change in the 

contact angle relative to the smooth surface on irradiation, 

contact angle hysteresis was also reduced on the rough surface 

so that a water droplet could be moved across it on 

application of an asymmetric irradiation. 

9. Artificial Biomolecular Machines 

9.1. Hybrid Biomolecular Motors 


Chemie 

Motor proteins provide both inspiration and important 

proofs-of-principle for the synthetic chemist trying to create 

artificial motor molecules. In turn,the increasing sophistication 

of the task carried out by synthetic structures may one 

day (perhaps sooner than one might think) start to aid our 

understanding of complex natural systems. However,the 

demonstration of such amazing mechanical functionality by 

motor proteins has also triggered a different approach to 

creating tiny mechanical devices: namely the direct application 

of complete biomolecular motor constructs in nonnatural 

settings. Initially,interfacing operational motor proteins 

with artificial constructs was purely concerned with 

further dissecting the mechanochemical mechanisms of the 

natural systems. In a series of experiments which have 

achieved classic status,direct observation of directional 

rotation of the F1-ATPase motor,driven by ATP hydrolysis, 

was realized for individual motors mounted on glass, [543] while 

the transmission of this motion to the F0 motor in complete 

F0F1-ATPase constructs has also been observed. [544] The 

reverse process—ATP synthesis—has subsequently been 

achieved in a similar environment,by physically driving 

rotation of the F1 motor in the opposite direction to that 

observed for the hydrolysis reaction; this is the first demonstration 

of artificial chemical synthesis driven by a vectorial 

force! [545] 

Mimicry and deconvolution of natural systems aside, 

methods by which biomolecular motors can be reliably 

incorporated into artificial systems are being pursued to 

create nanomechanical systems powered by ready-made 

molecular motors. [546] Such endeavors constitute a research 

area in their own right, [547] 

involving,for example,the 

integration of soft organic functional molecules with hard 

inorganic components and supports; the genetic engineering 

of motor proteins to adapt their function and interaction with 

synthetic components; and the engineering of switches 

whereby the natural motor can be turned on or off. 

The use of myosin molecules immobilized on a solid 

substrate to transport actin strands across the surface was one 

of the earliest in vitro studies of motor protein mechanochemistry. 

[548] Analogous systems,many employing kinesin 

(or dynein) and microtubules as the motor and cargo 

components,respectively,are now being investigated with a 

view to practical applications. [549] The potential uses of such 

systems clearly include the transport of nanoscale cargoes and 

consequently the challenges of controlling and directing the 

motion,as well as capture and release of molecular materials, 

are actively being pursued. [1l,547a,c] As mentioned in Section 

8.3.3,temperature-responsive polymers can be used as 

control elements for motor proteins, [476] but recently it was 

shown that proteins themselves can be turned into novel 

polymer gel actuators. In particular,a chemically cross-linked 

actin gel has been shown to move over a cross-linked myosin 

gel in the presence of ATP,with speeds achieved similar to 

those of the native protein construct,thus opening up the 


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possibility of creating gel-based devices powered by protein 

motors rather than by osmotic effects. [550] 

As for fully synthetic systems,any macroscopic mechanical 

application of biomolecular motors is likely to require the 

parallel operation of a great number of molecular devices— 

just as limb movement in an animal is the result of the 

coordinated effort of many millions of myosin motors. 

Recently,the self-assembly of muscle cells on silicon microdevices 

has been achieved. The advantage of using whole cells 

(cardiomyocytes in this case) to grow muscle bundles is that 

all the machinery for cooperative motion is automatically 

present and the result is the first microstructure which can 

move autonomously as a result of cooperative contraction of 

muscle bundles. [551] 

A related active field is that of biomolecular electronics,in 

which native and genetically engineered proteins are 

deployed in molecular-based electronic and photonic devices. 

In many cases the electronic switching mechanism involves 

molecular-level motion,exemplified in particular by systems 

which rely on the photochromic and photoelectric properties 

of bacteriorhodopsin. [552] 

9.2. Hybrid Membrane-Bound Machines 

The development of synthetic ionophores and ion channels 

has been a central goal of supramolecular chemistry for a 

number of decades and advanced functionality such as 

enantioselection and stimuli-controlled transport has been 

achieved. [553] Recently,however,biological channel proteins 

have been used in artificial settings and external control over 

their functions achieved. The mechanosensitive channel of 

large conductance (MscL) from Escherichia coli is a homopentameric 

protein channel which opens in response to 

internal pressure within the bacterium,thus allowing nonselective 

efflux of ions and small solutes. [554] It is known, 

however,that the introduction of polar or charged residues at 

a specific location in the protein can result in spontaneous 

opening of the pore. [555] Incorporation of a cysteine residue at 

this crucial amino acid position provided a handle to which 

Feringa and co-workers could attach artificial photoswitches, 

thereby creating light-switchable versions of this system. [556] 

In the first instance,an acetate unit protected by a photocleavable 

group was attached to the cysteine residue (Scheme 

89a) and the resulting hybrid (146) incorporated in a synthetic 

lipid membrane. Photolysis of the protecting group revealed 

free acetate units,and concomitant opening of the channels 

was clearly observed on the single-molecule level by using 

patch-clamp techniques. A reversible analogue was created 

by appending a spiropyran switch to the cysteine residue 

(giving SP-147,Scheme 89b). Opening and closing of the 

channel was observed again in patch-clamp experiments, 

however,a significant decrease in the number of pores 

opening was observed on repeating the procedure for a 

second time. An efflux experiment was performed in which a 

self-quenching dye was released from liposomes on opening 

the channel. A clear increase in permeability on irradiation 

was demonstrated,although some leakage from the “closed” 

channels was also observed. A related approach has 


Scheme 89. Chemical structures of the photochromic switches used to 

create: a) irreversible and b) reversible light-triggered MscL. [556] As the 

MscL construct is a homopentamer, each channel features five sites 

for attachment of the photochromic units. SP = spiropyran form, 

MC = merocyanine form. 

employed azobenzene chromophores to reversibly place a 

blocking group in Shaker K + ion channels in rat hippocampal 

neurons [557] and to bring an agonist into contact with the 

binding site in a ligand-gated ion channel,again in living 

cells. [558] The latter could,in principle,be a general method for 

creating optically switchable versions of many allosterically 

regulated proteins. Rather than postsynthetic functionalization 

of amino acid side chains,photoswitches can also be 

incorporated by chemical synthesis as non-natural amino 

acids in place of terminal residues. This approach has been 

used to create various photoswitchable analogues of the lowmolecular-weight 

channel-forming peptide gramicidin. [559] 

Artificial carrier mediated translocation of ions across a 

membrane can be coupled to redox reactions so that the 

carrier is oxidized and reduced at opposite sides of the 

membrane,thus adjusting its affinity for the transported 

species depending on its location. [560] A particularly impressive 

extension of this concept draws on the mechanism of 

photosynthetic energy conversion in nature—the photogeneration 

of charge-separated states. [561] Artificial photosynthetic 

reaction center 148 (Scheme 90) exploits components 

commonly used by nature—a porphyrin photosensitizer (P),a 

carotenoid polyene electron donor (D),and a naphthoquinone 

electron acceptor—to create charge-separated states of 

the form D + C-P-A C. Directionally inserting 148 into liposome 

membranes results in a transmembrane electrochemical 

potential on irradiation with light. This allows the spatial 

control of the oxidation state for quinone-based carrier 

molecules which are dissolved and freely diffusing in the 

membrane. The change in oxidation state switches the 

pK a value [562] or the calcium ion binding affinity [563] of the 

carrier molecules,depending on their proximity to the inner 

or outer surface of the membrane,so as to facilitate proton or 

calcium ion pumping across these “artificial photosynthetic 

membranes”. Continual operation of the proton transport 

system and concomitant generation of a protonmotive force 



Scheme 90. Artificial photosynthetic reaction center 148 which was used to create a transmembrane electric potential so as to power proton [562,564] 

or calcium [563] transport. 

was illustrated by incorporation of intact F 0F 1-ATPase into 

the artificial photosynthetic membrane,and in vitro ATP 

synthesis was successfully demonstrated. [564] 

These systems harness directional electron transfer to set 

up the electrochemical gradient necessary for ion transport. 

They therefore correspond to the redox-loop (or Mitchellloop) 

mechanisms for transport in nature (Section 1.3). [33] 

Synthetic examples of conformational pumps,on the other 

hand,have not yet been realized,although the design of 

potential components is being actively pursued. [565] 

9.3. DNA-Based Switches and Motors: Molecules that Can Walk 

It is also possible to borrow from nature,not the 

completed machine or some components thereof,but the 

materials used to build them. The use of nucleic acids as 

nanoscale construction materials have been exquisitely demonstrated 

over the past decade in a variety of ways. [566,567] 

Following an initial report on the control of double-stranded 

DNA branch migration, [568] the first artificial,well-defined, 

large amplitude DNA-based conformational switch was 

achieved by harnessing the ability of certain DNA sequences 

to change between right-handed B forms and left-handed 

Z forms,depending on the nature of the environment. [569] One 

such sequence was used to connect two rigid DNA doublecrossover 

motifs to create a linear mechanical device. The B– 

Z transition results in a twisting of the device around the 

central unit (as well as a small change in length),thereby 

altering the separation of equivalent points on the two 

double-crossover units. This reversible process was monitored 

by fluorescence resonance energy transfer (FRET) between 

dyes attached to the double-crossover portions. [569] 

The system depicted in Figure 53 is not only constructed 

from DNA but is also operated by the addition of specific 

oligonucleotide sequences. Three DNA strands (A, B,and C) 

self-assemble to give the “relaxed” structure. A fourth strand, 

the “fuel” F,has sequences complementary to the singlestranded 

regions of both A (red) and B (blue),and so 

hybridization occurs to give the “closed” form. However, F 

also contains an eight-base overhang (pink) at its 3’ end. This 

acts as a “toehold” for a “removal” strand R,which is 

complementary to the full length of F. Binding at the 


Chemie 

Figure 53. Operation of a pair of DNA tweezers. [570] Closing of the 

tweezers amounts to bringing the two rigid double-stranded regions 

(black) close together by hybridization of a fuel strand F. Removal of 

the fuel strand to restore the relaxed state is brought about by addition 

of a removal strand R, which binds initially at the toehold on F, then 

branch migration leads to complete removal of F from the device with 

concomitant formation of one molecule of duplex waste FR. The 

coloring scheme indicates the complementary regions on different 

threads; lines indicating base paring are purely schematic and do not 

represent a particular number of bases. TET = 5’-tetrachlorofluorescein 

phosphoramidite; TAMRA = carboxytetramethylrhodamine. 

overhang is followed by continuing hybridization along the 

length of the two strands by a branch-migration process,until 

the inert “waste” duplex FR is formed and the machine 

returns to its original relaxed state. The process is reversible 

and reproducible over several cycles,as evidenced by FRET 

measurements which indicate a difference in the end–end 

distance between the two forms of approximately 6 nm. [570] A 

related device adopts the same strategy to switch between a 

relaxed state and an “open” state,where addition of the fuel 

strand results in an approximately linear conformation. [571] 

Finally,these two systems were combined to create a threestate 

device capable of switching repeatedly between conformationally 

well-defined open and closed forms through the 

more flexible relaxed state. [572] Switching between two welldefined 

conformations triggered by hybridization has also 

been achieved in an alternative system based on crossover 

motifs. [573] In this case,a 1808 rotation of one end of a linear 

device relative to the other end results. One-dimensional 

oligomeric arrays of such devices were prepared,with a 

structurally rigid DNA substituent appended to each monomer. 

The switching motion could then be observed by AFM as 

a change in the relative orientation of the rigid subunits. A 


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Reviews 

related system has since been designed to exhibit lengthening 

and contraction of a linear DNA construct. [574] This device was 

incorporated into a 2D DNA lattice and its switching used to 

reversibly alter the dimensions of the lattice features,again 

evidenced by AFM. 

Opening and closing or twisting of DNA devices could 

clearly be used to alter the relative orientations of a wide 

number of attached functionalities,in a manner similar to 

rotaxane-based co-conformational switches (Section 8.2.2), 

while it has also been postulated that these devices may be 

able to exert mechanical forces,again similar to the shuttlebased 

switches (Section 8.3.3). The use of specific oligonucleotides 

to trigger the molecular-level motion may have 

advantages for the development of more complex systems, 

where it should be possible to construct machines composed 

of a variety of subtly different molecular components. Each 

could then be selectively triggered by a specific oligonucleotide 

stimulus,allowing the fuel to act also as an information 

carrier between the operator and machine,or even between 

different machine components. On the downside,however, 

each operational cycle results in the production of a waste 

duplex strand and,from a practical point of view,dilution of 

the system. Both these factors have been shown to result in a 

decrease in the fluorescent response on increasing cycles. 

Furthermore,the hybridization processes are relatively slow: 

half-times for completion of these reactions are commonly of 

the order of tens of seconds. On the other hand,a DNA 

conformational switch which operates simply by adding and 

removing protons has now been created (Figure 54). [575] 

Certain cytosine-rich strands become partially protonated at 

low pH values and form a compact quadruplex structure 

known as the i motif. Raising the pH value disrupts this 

structure,thereby allowing the single-stranded DNA to be 

captured by a partially complementary strand waiting in 

solution,thus forming an extended duplex structure,as 

evidenced by a decrease in the FRET response between two 

attached dyes. If the binding between the two strands is not 

too strong,the generation of an acidic environment reforms 

the i motif. The system exhibits impressive fatigue resistance 


even after 30 cycles,while the switching processes both occur 

in about 5 s. [576] Two related triplex–duplex contraction– 

expansion systems,also triggered by controlling cytosine 

protonation,have also been reported. [577] Both are fully selfcontained 

devices in which all the oligonucleotides (two 

stands in one case,three strands in the other) remain 

associated in both open and closed forms. Quadruplex– 

duplex contraction–expansion systems have also been achieved 

by using the competitive hybridization strategies 

discussed above, [578] and this has been combined with aptamer 

technology to create a device in which binding and release of 

a protein (the human blood clotting factor a-thrombin) can be 

reversibly achieved. [579] It is worth noting that these contraction–expansion 

systems bear some resemblance to the switchable 

helical oligomeric systems discussed in Section 2.1.4. 

In most of the switches and motors we have discussed so 

far,at least two stimuli,applied consecutively,are required to 

send the machine through an operating cycle. A DNA-based 

open–closed conformational switch has been created,however,which 

can continuously cycle between two states 

without any external intervention as long as its fuel is 

present. [580] The two-stranded cyclic structure (Figure 55) 

consists of two duplex arms connected by a single base 

“hinge” at one end and a longer single-stranded region at the 

other. The 29-base single-stranded region (E) contains an 

RNA-cleaving 10–23 DNA enzyme (light blue) and in the 

absence of substrate (and in the presence of divalent cations) 

Figure 54. pH-switched quadruplex–duplex switching in a DNA molecular 

machine. [575] In acidic environments, the cytosine-rich strand A is 

partially protonated and forms the four-stranded self-complementary 

i motif. This holds the two dyes in proximity and FRET occurs. 

Increasing the pH value turns off the self-complementary interactions 

(blue!red) and the strand can now be captured by a partially 

complementary partner (B), thereby forming an extended duplex 

structure which holds the fluorophore and quencher units far apart 

and reducing the FRET response. The coloring scheme indicates the 

complementary regions on different threads; lines indicating base 

paring are purely schematic and do not represent a particular number 

of bases. Figure 55. An autonomous DNA machine. [580, 581] The machine consists 

of two single strands (D and E). The single-stranded 10–23 DNAzyme 

region (light blue) of E adopts a coiled-coil conformation so that the 

machine adopts a closed arrangement. Binding of a DNA–RNA 

chimera substrate (S) forces the machine to adopt an open state. 

Subsequent enzymatic action on the substrate creates two products 

(S 1 and S 2 ), each of which only has weak complementarity for the 

enzyme strand and so are released in favor of the closed conformation. 

Addition of an all-DNA strand B which is complementary to the activesite 

region, also forces formation of the open conformation, but halts 

enzyme action until B is removed by competitive hybridization using 

removal strand R. The coloring scheme indicates the complementary 

regions on different threads; lines indicating base paring are purely 

schematic and do not represent a particular number of bases. 



it exists in a coiled-coil conformation which gives an overall 

closed state for the device. Substrates (S) for the DNAzyme 

are DNA–RNA chimeras complementary to regions either 

side of the catalytic site so that hybridization forces the 

structure to adopt an open arrangement. Cleavage of the 

substrate ensues and produces two fragments (S 1 and S 2 ), 

neither of which bind strongly to E and so are ejected in favor 

of forming the compact closed state once more. The device is 

now ready to undergo a second cycle of opening and closing 

and will continue to do so,without any external control,until 

no substrate “fuel” is left. 

Also illustrated in Figure 55 is an external control 

mechanism whereby the autonomous machine can be 

switched on or off by addition or removal of a “brake” 

strand (B),which has greater affinity for E than the substrate 

but cannot itself be cleaved. [581] A different autonomous 

device has been realized based on the elegant use of topology 

to kinetically hinder a competitive hybridization reaction. [582] 

In this case,the “device” is simply a short oligonucleotide 

which oscillates between a random single-stranded state and a 

more-ordered duplex state. 

As with the small-molecule organic systems,a key 

challenge for DNA-based machines is achieving directional 

processive motion,either in a linear or rotary form. In this 

regard,successful systems have recently been demonstrated 

by four independent research groups. [583] The first of these, 

from Sherman and Seeman,is shown in Figure 56. [584] A triplecrossover 

molecule acts as a rigid track from which protrudes 

Figure 56. A non-autonomous DNA walker which moves using an 

inchworm-like gait. [584] Matching colors indicate complementary 

sequences between the strands; lines indicating base paring are purely 

schematic and do not represent a particular number of bases. a) The 

walker starts off attached to the track through both “feet”, by means of 

“set” strands which each have regions complementary to the appropriate 

foot and “foothold” on the track. b) The front foot is released by 

removal of the appropriate set strand through competitive hybridization, 

initiated at a single-stranded toehold region (pink) on the set 

strand. The removal strand has biotin attached so that the resultant 

duplex waste can be easily removed. c) The front foot is attached to 

the next foothold on the track using a set strand of appropriate 

sequence. d) The rear foot is now released by competitive hybridization 

of its set strand. e) Finally, the rear foot is attached at its new 

position by the required set strand. 


Chemie 

a series of three single-stranded “footholds” (red,green,and 

light blue). A bipedal walking device is constructed from two 

helical domains (“legs”),each with a single-stranded “foot” 

(dark blue and orange) at one end and connected together by 

flexible linkers at the other. Attachment of the walker to the 

track occurs through “set” strands which have a specific footcomplementary 

sequence adjacent to a specific footholdcomplementary 

sequence. Starting with both feet anchored to 

the track (Figure 56 a),the “front” foot can be lifted by 

removing its set strand (Figure 56b). This is done by 

competitive hybridization initiated at a toehold region 

(pink) as discussed for the simpler machines above. Addition 

of a different set strand then anchors this foot to the next 

foothold (Figure 56 c). Finally,the rear foot is freed (Figure 

56d) and attached to the foothold just vacated by the 

front foot (Figure 56e). The walker can be returned to the 

starting position by a similar series of steps. Such a process, 

with the rear leg always trailing,has been described as an 

“inchworm” gait (see Section 4.4). The present system only 

contains three footholds and so there is no choice of direction 

for the walker to make at any stage; it is a positional switch 

rather than a motor. However,it may be possible to generate 

continued directional motion simply with a repeating 

sequence of three attachment points. It must be noted that 

the nature of the flexible linkers between the two legs is 

crucial here: they must be able to stretch across,say,the green 

foothold to link the red and light blue sites,but not so flexible 

as to allow motion in the wrong direction through passing of 

the front foot to the rear and attachment at a foothold on this 

side. 

A similar strategy was used by Shin and Pierce to create a 

bipedal walker (Figure 57) that moves with a gait in which the 

rear leg advances to the front (a “passing-leg” gait,see 

Figure 57. A non-autonomous DNA walker with a “passing-leg” 

gait. [585] Matching colors indicate complementary sequences between 

strands; lines indicating base paring are purely schematic and do not 

represent a particular number of bases. A sequence of removal strand 

and set strand additions removes the rear foot and reattaches it at the 

next foothold in front of the walker (see text for details). Each foothold 

is appended with a different fluorophore (not shown) and each foot a 

quencher, so that progression of the walker can be monitored by 

multiplexed fluorescence quenching measurements. 


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Reviews 

Section 4.4). [585] The track was constructed from six oligonucleotides 

which form a helical scaffold from which four 20base 

single-stranded footholds (red,green,light-blue,and 

yellow) protrude at regular intervals. The walker consists of 

two partially complementary oligonucleotides which form a 

20-base helix at one end,leaving two 23-base single-stranded 

legs (dark blue and orange). A sequence of set-strandmediated 

attachment and removal by competitive hybridization 

results in unidirectional walking of the device,as 

illustrated in Figure 57. 

A pair of DNA-based “gears” which can rotate unidirectionally 

against each other has been created by Ye and Mao 

by using the same principles (Figure 58). [586] This system 

comprises two DNA duplex circles composed of a central 

cyclic strand surrounded by three different linear strands, 

each of which has a single-stranded “tooth” at one end. The 

two gears can be connected through one tooth on each by a 

suitable set strand. The addition of a second set strand can 

attach the gears between two of the remaining teeth. Removal 

of the original set strand leaves a single linkage between the 

two gears again,but rotated by 1208 with respect to the 

starting point. The process can be continued in either 

direction to generate a full 3608 rotation. 

A number of approaches for achieving an autonomously 

processive DNA-based device have been proposed, [587] and 

the first such system was recently reported by Turberfield and 

Figure 58. Unidirectional correlated rotation of a pair of DNA-based gears, driven by 

hybridization reactions. [586] Matching colors indicate complementary sequences 

between strands; lines indicating base paring are purely schematic and do not 

represent a particular number of bases. 

co-workers. [588] In this case,the walker is a 6-base fragment of 

DNA (colored red in Figure 59) which moves along three 

footholds on a track through a series of ligation and 

restriction steps catalyzed by a ligase and two different 

restriction endonucleases. In the initial state the walker is 

ligated to foothold A. However,it has a 3-base sticky end 

which is complementary to the single-stranded overhang of 

foothold B. The flexible single-stranded regions at the base of 

each foothold allows hybridization of the complementary 

components (Figure 59b),thus creating a substrate for T4 

ligase and resulting in covalent attachment of the two DNA 


Figure 59. A unidirectional autonomous DNA walker. [588] The walker 

consists of the six-nucleotide base sequence colored red. Covalent 

attachment of the walker to a foothold is indicated by an asterisk; 

bridging between two footholds by hybridization is indicated by a plus 

sign; covalent attachment of the walker between two footholds is 

indicated thus: X*Y. In practice, the sequences of footholds A and C 

are identical. Lines indicating base paring are purely schematic and do 

not represent a particular number of bases. 

fragments (giving A*B,Figure 59c). In turn,this creates a 

recognition site for a restriction enzyme (PflM 1). Crucially,the 

selectivity of the resulting cleavage is such that 

the walker is always transferred onto foothold B (Figure 

59d) and the restriction site is destroyed. This means 

that although B* and A may associate again through 

hybridization (giving A + B*,Figure 59 e),and ligation 

may occur to give A*B once more,this is simply an 

“idling” step as subsequent cleavage can only restore B* 

once more: the motion is essentially ratcheted by the 

selectivity of the restriction endonuclease. Foothold C has 

the same overhanging three bases as foothold A,however, 

and so hybridization in this “forward” direction may occur 

(giving B* + C,Figure 59 f). The complex formed is again 

a substrate for T4 ligase,so B*C is produced (Figure 59 g). 

This creates a substrate for a second restriction endonuclease,BstAP 

1,and cleavage occurs to give C* (Figure 

59h). Again,an idling step involving religation with B 

may occur,but cleavage to give B* does not follow and so 

the motion cannot be reversed. This device then is an 

interesting example of an information ratchet (see Section 

1.4.2). The free energy of the device at states A*, B*, 

or C* is virtually identical and invariant,and the directionality 

of motion is achieved irrespective of what foothold is 

occupied,with the kinetics for passage in one direction (left 

to right as drawn) being faster than passage in the opposite 

direction. 

Two further autonomous walking systems have also been 

reported. [589,590] Both these machines involve tracks which 

display essentially identical footholds for the walker,together 

with a single enzyme which is able to cleave portions of the 



track only when the walker is bound. In one case, [589] a nicking 

enzyme is employed (Figure 60). This is a restriction endonuclease 

which binds double-stranded DNA at a specific 

sequence but then catalyzes the cleavage of only one strand. 

Figure 60. An autonomous DNA walker (red) starting midway through 

its journey from left to right. [589] Lines indicating base paring are purely 

schematic and do not represent a particular number of bases. 

Hybridization of the walker oligonucleotide to a singlestranded 

foothold on the track provides the correct recognition 

sequence for the enzyme (Figure 60a),which subsequently 

cleaves the foothold strand eight bases from its end 

(Figure 60 b). The resultant eight-base duplex has a melting 

temperature below the operating temperature of the device, 

so dissociation occurs (Figure 60c) to reveal an overhang on 

the walker through which it can seek (Figure 60 d)—and then 

bind to—the next foothold along the track (Figure 60 d!e). 

Motion continues in this way,with movement in the “backwards” 

direction prevented by the irreversible cleavage of 

each successive foothold. The walker can be stopped on any 

foothold by introducing a single mismatch in the enzyme 

recognition site. In the second example, [590] the walker itself is 

the enzyme—a 10–23 DNAzyme,similar to that used in the 

autonomous tweezers (Figure 55). The footholds are provided 

by DNA–RNA chimeras and duplex formation with the 

walker results directly in cleavage of the foothold between 

two RNA residues. In a manner similar to the previous 

example,this frees a portion of the walker to seek out the next 

foothold with which it can fully associate. Just like the 

autonomous walker in Figure 59,both these systems operate 

by imposing an almost infinite barrier to motion in the 

“backwards” direction. Unlike the first example,however, 

these systems completely destroy the track in their wake—the 

motion is entirely irreversible and the track not reusable— 

while waste oligonucleotides are produced in each cleavage 

step. [591] 

The rapid progress in DNA-based molecular machines is 

testament to the power of this precisely programmable selfassembling 

construction and information-bearing material. 

[592] In living systems,oligonucleotides carry out a variety 

of roles within highly complex environments and the next 

advances in the artificial systems will surely see integration of 

these relatively simple machines,which exploit the structural 

properties of the material,with other emerging nucleotidebased 

technologies. Already a DNA tweezer device,closely 

related to that depicted in Figure 53,has been integrated with 

genetic DNA. [593] In this system,the genetic material is 

transcribed and produces a strand of mRNA which acts as the 

fuel strand,thereby closing the tweezers in an autonomous 

fashion. A similar process could be used to generate the 

removal strand,while mechanisms for regulating gene transcription 

have also been incorporated. The use of DNA as a 

templating scaffold for carrying out covalent chemistry is 

another emerging area where DNA switching technology has 

already been applied. [594] Here,a pH-controlled duplex– 

triplex switch is able to swap the reactivity of two chemically 

similar amines in an acylation reaction with a carboxylic acid. 

Furthermore,the machines described above exploit only a 

fraction of the structural characteristics and abilities of DNA, 

while DNA-templated assembly and nanofabrication of other 

materials is also of great interest. [566a,f–h,592,595] The recognition 

and mechanical properties of DNA have recently been 

exploited in a number of sensor systems. In particular, 

fluorophore-labeled DNA hairpins—so-called “molecular 

beacons”—are capable of very sensitive and specific detection 

of oligonucleotides. [596] The ability of certain DNA 

sequences to bind specific proteins,often resulting in a 

conformational change,has been exploited in a DNA-based 

device which can estimate binding free energies through a 

nanomechanical mechanism. [597] In another example,a DNA 

aptamer was combined with a fluorescently labeled,complementary 

oligonucleotide strand so that binding of the aptamer 

to its target (adenosine,in this case) is signaled by release of 

the tagged strand. [598] The released strand can then be 

designed to hybridize with another oligonucleotide in 

response to the analyte,while introduction of an enzyme 

that reacts with the guest molecule can reset the system. 

Indeed,the ability of oligonucleotides to selectively recognize 

specific sequences amongst a milieu of other molecular 

“noise”,together with the highly refined enzymatic tools of 

molecular biology,form the basis of a rapidly increasing 

number of systems in which DNA molecules are used to 

perform logic and computational functions,both in vitro, [599] 

and in living cells. [600] Such networks may prove important in 

the control of more sophisticated DNA-based mechanical 

devices. 

10. Conclusions and Outlook 


Chemie 

In this Review we have outlined the current state-of-theart 

with regards to how the relative positioning of the 

components of molecular-level structures can be switched, 

rotated,speeded up,slowed down,and directionally driven in 

response to stimuli. In doing so they can affect the nanoscopic 

and macroscopic properties of the system to which they 

belong. Whether one chooses to call such structures “motors” 

and “machines”,or prefers to consider them more classically 

as specific triggered large amplitude conformational,configurational,and 

structural changes,is irrelevant. What is 


163

Reviews 

important is that the use of controlled molecular-level motion 

to bring about property changes is fundamentally different— 

both in terms of how to do it and in what it can do—to 

methods that rely solely upon variations in the nature of 

functional groups or electrostatics. 

Currently it is fair to say that there are two distinct design 

philosophies being used to try and prepare synthetic molecular-level 

machines: The first “hard matter” approach focuses 

on adapting mechanical principles and designs from the 

macroscopic world to molecules and is typified by the 

research efforts on field-driven rotors,molecular gyroscopes, 

molecular scissors,molecular wheelbarrows,nanocars,etc. In 

this approach,friction and binding interactions are avoided as 

much as possible and the molecules are designed to be rigid in 

all degrees of freedom except those involved in the desired 

motion. The input energy is designed to provide a directed 

force that pushes the molecular machine in the desired 

direction or exerts a torque to cause it to turn. This approach 

follows directly from that used in the design of macroscopic 

machines,which are designed to reduce friction and sticking 

and to eliminate jitter,vibration,and excess motion that 

dissipate energy and reduce the efficiency of the machine. 

The second “soft matter” approach is more chemical in 

philosophy and seeks to adapt principles of chemistry 

(selective stabilization and destabilization of noncovalent 

bonding interactions,structural symmetry,and kinetic versus 

thermodynamic control of processes) to achieve efficient and 

controllable directional motion at the molecular level. This 

approach characterizes our own studies on catenanes and 

rotaxanes,for example,and also that of the DNA walkers,etc. 

Directed motion is achieved by a sequence of reactions in 

which different covalent and noncovalent-bonding arrangements 

are alternately stabilized and destabilized. The input 

energy is used to ensure that the sequence of reactions occurs 

in one order and not the reverse. The motion occurs by 

diffusion over an energy barrier,where the conformational 

changes are best described as thermally activated transitions 

from states that are in local equilibrium. 

The advantage of the “hard matter” approach is that we 

understand macroscopic mechanics very well and so can 

easily see how to construct mechanical machines. The 

disadvantage is that,under most conditions,such machines 

must fight against the physics and chemistry intrinsic to their 

length scale. The advantage of the “soft matter” approach is 

that by using the principles outlined in Sections 1.4.2,1.4.3, 

and 4.4 we can see how to exploit the natural features of the 

nanoscale environment. Its disadvantage is that there is no 

familiar macroscopic model to follow and nature s exquisite 

working examples are too complex in their detail to provide 

us with more than broad clues at present. 

As outlined in this Review,both sets of design philosophies 

have already had many notable successes and they are 

not mutually exclusive. No doubt their combination will 

become increasingly important in the future. 

Unfortunately,the hype surrounding science fictional 

“surgical nanobots” and the hysteria of “grey goo”,has led to 

controversy and the questioning of expectations for synthetic 

molecular machines. In a commentary [601] on the exciting 

recent developments in catalytically driven microparticles 


(Section 6.1) the question was posed “What is the problem 

that requires having a nanomotor?”. Perhaps the best way to 

appreciate the technological potential of controlled molecular-level 

motion it is to recognize that this question has been 

asked and answered repeatedly over four billion years of 

evolution with the result that nanomotors and molecular-level 

machines lie at the heart of virtually every significant 

biological process. Nature has not repeatedly chosen this 

solution without good reason. In stark contrast to biology, 

none of mankind s fantastic myriad of present day technologies 

(with the exception of liquid crystals) exploit controlled 

molecular-level motion in any way at all. When we learn how 

to build synthetic structures that can rectify random dynamic 

processes and interface their effects directly with other 

molecular-level substructures and the outside world,it has 

the potential to revolutionize every aspect of functional 

molecule and materials design. An improved understanding 

of physics and biology will surely also follow. 

In this regard,we do not subscribe to the view that it will 

be impossible for synthetic chemists to develop molecularlevel 

machine systems that use controlled motion to perform 

functions similar to those of biological machines simply 

because of the complexity of the latter (just as the tremendous 

successes in homogeneous and heterogeneous catalysis have 

been achieved without the need for the de novo design of 

enzymes). The first examples of molecular-level mechanical 

switching being used to perform functions on surfaces and in 

solution have already been demonstrated. However,a broad 

new range of synthetic strategies and methodologies are 

needed to take this further. It is only in the last decade that 

unnatural product synthesis has progressed to a level where 

the architectures necessary for biasing conformational and coconformational 

motions can be constructed. However,this is 

not,in itself,enough to produce anything other than the most 

basic molecular-machine systems. Any machine more sophisticated 

than a switch must operate by manipulating nonequilibrium 

conformations and/or co-conformations of a 

substrate or itself. Although many methods for turning 

binding interactions “on” and “off” have been developed, 

relatively little is known about how to vary the kinetics of 

binding in response to external stimuli,and virtually nothing 

about how to do so in systems where the substrate is restricted 

from exchanging with the bulk. 

Sections 2.1.2,2.2,and 4.6 discussed the first examples of 

unidirectional motors based on rotation around single, 

double,and mechanical bonds,respectively. The development 

of molecular-level systems which carry out functions by 

responding to stimuli through Boolean logic operations [252] 

has clear relevance to the future development of interfaced 

and compartmentalized molecular machines which are more 

sophisticated than the current generation of mechanical 

switches and motors. While current efforts in molecular 

logic have concentrated on supramolecular systems rather 

than mechanical motion,their success suggests a way in which 

relatively simple molecular-machine components might be 

connected to produce useful devices at the next level of 

complexity (Section 4.4). 

Developments in synthetic chemistry almost always go 

hand-in-hand with advances in measurement and instrumen- 



tation. Spectacular advances in spectroscopy [602] and singlemolecule 

manipulation techniques (see Section 7) have 

already had a major impact in the study of molecular-level 

machine systems and further breakthroughs appear more 

than likely over the next few years. 

Despite the intrinsic simplicity of the current generation 

of synthetic molecular machines,attention is already turning 

to their application to perform useful tasks. Inspiration and 

assistance again comes from an increasing understanding of 

biological motor proteins and information processing,as well 

as the remarkable achievements of modern-day microelectronics 

and mechanical engineering. Yet we must bear in mind 

that mechanically based devices made by the synthetic 

chemist will have different characteristics,strengths,and 

weaknesses to their counterparts at other length scales. As 

with many fundamental developments in science—from 

electricity to manned-flight,the computer and the internet—it 

is not clear at the very beginning (and make no 

mistake that we are,indeed,at the very beginning in terms of 

experimental systems) in exactly what ways synthetic molecular-level 

machines are going to change technology. In the 

short term,changing surface properties,switching,and 

memory devices look particularly attractive. A greater 

challenge,however,is to transduce the energy input from 

an external source to a molecular machine into the directed 

transport of a cargo or the pumping of a substrate to reverse a 

chemical gradient. The organization and addressing of 

molecular machines on surfaces and at interfaces is an area 

where we can expect particularly important advances over the 

next few years. 

The breadth of this Review is testament to the multidisciplinary 

nature of the subject matter. We hope it will be of 

interest to biologists to see what insights simpler molecular 

analogues might have for uncovering the workings of complex 

motor proteins. We hope it will be of interest to mathematicians 

and physicists to see what synthetic chemists can make 

(and cannot yet make) and the molecular design strategies 

that can be gleaned from their theories. We hope it will be of 

interest to materials and surface scientists to see what 

molecular-machine structures are available,which they can 

consider trying to organize,characterize,and utilize. We hope 

it will be of interest to engineers to see the kinds of property 

effects possible,and the stimuli that can be used,with 

molecules that need to be interfaced with the outside world. 

But most of all we hope it will of interest to chemists— 

synthetic,organic,inorganic,physical,and theoretical—and 

that it might inspire them to take up a challenge in which the 

rules of the game are only just being appreciated,and where 

there is much virgin territory to be trodden and major 

breakthroughs to be made. 

Addendum (September 22, 2006) 

In the time since this Review was accepted for publication,progress 

in the field has continued apace. The general 

importance and broad appeal of synthetic molecular 

machines has been reflected in the regular appearance of 

various short review articles focusing on the most recent 


Chemie 

advances in specific areas of the field,including: conformational 

switching in cavitands, [603] conformational control by 

stereochemical relays, [604] switching of chiral properties, [605] 

light-stimulated machines, [606] switchable molecular shuttles, 

[607] transition-metal-based molecular machines, [608] crystalline 

molecular machines, [609] self-locomotion, [610] electromechanical 

molecular electronic devices, [611] liquid-crystalline 

phase alignment, [612] liquid-crystalline elastomer actuators, [613] 

and biomotors used to power self-assembly processes. [614] 

Recent experiment and theory has shown that interesting 

effects arise for ratchet systems in which there are several 

interacting particles moving over the same potential-energy 

surface. [615] This brings to mind the almost complete absence 

of polyrotaxane architectures from current synthetic molecular 

machine designs and suggests that these interlocked 

architectures may provide interesting systems in the future. 

Even today,the long-studied concept of correlated conformational 

motions continues to generate significant interest and 

advances, [616] 

including an investigation of a molecularorbital-controlled 

gearing effect during a sigmatropic rearrangement. 

[616c] The more recent concept of molecular “gyroscope” 

structures has also seen new examples reported,with 

potentially interesting dynamic features. [617] Observed at the 

single-molecule level using STM,rotation of a porphyrinbased 

molecule on a silver surface has been shown to be 

reversibly switched on by addition of a small “hub” molecule. 

[618] Using an overcrowded alkene,a three-state luminescent 

switch has been demonstrated,whereby red-,blue-,and 

nonfluorescent states can be accessed by appropriate application 

of light,heat,and electrons. [619] Continuing the systematic 

investigation of unidirectional motors constructed from 

overcrowded alkenes,new members of the “second generation” 

series have been reported, [620] including the fastestrotating 

example yet. 

Understanding and characterization of isolated molecular 

mechanical switching units is now such that devices of greater 

complexity,incorporating a number of fundamental features, 

are within reach. Aida and co-workers have harnessed an 

azobenzene isomerization-induced change in conformation 

around a metallocene pivot to control the relative arrangement 

of two porphyrin substituents. These,in turn,can 

regulate the conformation of a kinetically bound guest. [621] In 

a related system,a photoresponsive guest has been used to 

switch the host molecule between two,kinetically stable, 

conformations. [622] An example of macroscopic-machineinspired 

design can be found in a report on the construction 

and solution-phase characterization of an ambitious new 

member in the molecular “nanocar” series that combines the 

design features of the original STM-tip-driven molecules with 

an overcrowded alkene molecular motor as a proposed 

propulsion mechanism. [623] 

In terms of rotaxane-based switches,recent advances 

include: the first quantitative force spectroscopy measurements 

on intercomponent interactions in a shuttle; [624] further 

characterization of amphiphilic shuttles arranged at the air– 

water interface [625] and the fabrication of solid-state electronic 

devices from monolayers; [626] theoretical and experimental 

work aimed at further clarifying the mechanism of operation 

for solid-state MSTJs; [627] and progress towards an electrically 


165

Reviews 

powered actuator constructed from such rotaxanes. [628] In a 

truly novel addition to the dynamic interlocked molecules 

field,a rotaxane has been reported in which raising the 

temperature leads to reduced intercomponent motions,as a 

result of the reversible formation of imine bonds between the 

macrocycle and thread. [629] 

Mechanical [630] 

and electrostatic [631] 

telescoping of 

MWNTs has recently been exploited to create a tunable 

nanoresonator and a nanoelectromechanical switch,respectively. 

Polymer-based actuator materials have continued their 

march towards useful devices,making progress on several 

fronts. The development of stimuli-responsive hydrogels that 

are biochemically degradable [632] and that respond to important 

biological analytes in relevant media [633] should prove to 

be important advances. In terms of engineering existing 

actuator materials,highlights include the use of stimuliresponsive 

hydrogels to control the focal length of liquid 

microlenses [634] and the direct conversion of chemical potential 

into work using charge- and heat-powered actuator 

materials by creating fuel-cell electrodes from carbon nanotube 

sheets and a shape memory alloy,respectively. [635] 

In an interesting experiment,STM has been applied to 

investigate conformational changes in single chlorophyll-a 

molecules on injection of electrons,thus revealing a four-step 

switching scheme. [636] Further development of modified MscL 

channel proteins has led to a tunable pH-sensitive valve that 

may find application in drug-delivery systems, [637] while an 

entirely synthetic peptide has been used to form switchable 

channels which open in the presence of Fe(III) ions. [638] It has 

been shown that microtubules being transported down 

kinesin-coated channels can be directed at channel junctions 

by application of an electric field. [639] A pH-responsive 

conformational switch constructed from DNA has recently 

been attached to a solid substrate and coupled to an 

oscillating chemical reaction to power its operation. [640] 

Finally,a remarkable self-assembling system of aromatic 

chromophores has been shown to span a lipid bilayer and 

generate a photoinduced electric potential. This was used to 

power the reduction of quinones held inside vesicles formed 

by the membrane,thereby resulting in a transmembrane 

proton gradient. Addition of an aromatic intercalator irreversibly 

disrupted the complex,turning it into an ion channel 

through which the proton gradient could equilibrate. [641] If this 

is not quite a synthetic ion pump,it is well on the way there! 

The first four decades of supramolecular chemistry were 

primarily concerned with the manipulation of molecular-level 

structures under thermodynamic control. [169] However,the 

most recent developments in molecular-level machines demonstrate 

yet again that to build sophisticated functional 

systems it will be necessary to develop a whole new field of 

supramolecular and molecular chemistry that operates,with 

control,far from equilibrium. The underlying principles that 

will allow chemists to do this are outlined in Sections 1.4.2, 

1.4.3,and 4.4. 

D.A.L. and F.Z. would like to thank all the members, past and 

present, of their research groups for their ideas, imagination, 

and enthusiasmover the past 15 years. We also thank the UK 

and Italian funding bodies, the EU, and the Carnegie Trust for 

their generous funding of our research programs in the area of 

molecular motors and machines. 

Received: December 5,2005 

Published online: November 29,2006 


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Chemie 

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analysis in which they quantified the statistical entropy loss 

on sorting the particles and showed this to be less than the 

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b) A. F. Rex,R. Larsen in Proceedings of the Workshop on 

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(“Brownian rectifier” and “stochastic ratchet” are also occasionally 

used). This reflects the fact that thermal energy,in the 

form of Brownian motion,is the source of randomization in 

such schemes. Although the latter term is more common in the 

recent literature,it has to be said that some researchers (see,for 

example,Refs. [39f–h]) prefer the former on the basis that 

“Brownian ratchet” was first coined (l) S. M. Simon,C. S. 

Peskin,G. F. Oster,Proc. Natl. Acad. Sci. USA 1992, 89,3770- 

3774) for the specific phenomenon of protein translocation 

through pores,during which Brownian motion is ratcheted by 

binding events on one side of the membrane. There can also be 

confusion between the terms “thermal ratchet” and “temperature 

ratchet”; the latter should properly be reserved only for 

ratchet systems that operate on the basis of temperature 

gradients,a subclass of thermal ratchets. We believe,therefore, 

that both force of numbers and the illustrative nature of the 

term “Brownian ratchet” commend it for use here,particularly 

as “Brownian motor” is commonly used to describe a machine 

which operates by such a mechanism (see Ref. [5]). 

[40] Randomizing influences other than Brownian motion can be 

used in ratchet mechanisms; for example,in quantum ratchets, 

quantum effects such as tunneling or electron-wave interference 

play this role; see,for example: H. Linke,T. E. Humphrey, 

P. E. Lindelof,A. Lofgren,R. Newbury,P. Omling,A. O. 

Sushkov,R. P. Taylor,H. Xu,Appl. Phys. A 2002, 75,237 – 246. 

[41] The source of spatial inversion symmetry breaking is most 

commonly an inherently asymmetric (or “ratchet”) potential. 

In certain cases,however,a symmetric potential is sufficient if 

the energy input (although unbiased) brings about spatial 

asymmetry. Also possible is spontaneous symmetry breaking in 

coupled symmetric systems driven away from equilibrium (not 

discussed here). Of course,spatial inversion symmetry may also 

be broken by a combination of the above. 

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application with respect to both biological systems and future 

technology,see: special issue on “Ratchets and Brownian 

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Thomas Johann Seebeck in 1821. An electric current flows in a 

circuit composed of two resistors which are held at different 

temperatures (the modern equivalent of such thermoelectric 

circuits is a thermogenerator,in which a semiconductor diode is 

held at a different temperature to the rest of a circuit). For this 

reason,particle transport over symmetric periodic potentials, 

driven by spatial variations in temperature,is also often known 

as a “Seebeck ratchet”. Clearly,such schemes also bear a close 

resemblance to Feynman s ratchet-and-pawl (Section 1.2.1) 

when T 1 ¼6 T 2 and,indeed,mathematical equivalence of the 

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[188] For examples of mechanical devices based on kinetically stable 

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[190] There are some examples of catenanes and rotaxanes constructed 

under thermodynamic control by using dynamic 

processes such as olefin metathesis or formation of an imine 

bond (see for example: R. L. E. Furlan,S. Otto,J. K. M. 

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references therein). Such systems cannot act as molecular 

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[191] For reviews on the development of interlocked molecules as 

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[192] Numbers in square brackets preceding the names of interlocked 

compounds indicate the number of mechanically 

interlocked species,for example,a [2]rotaxane consists of a 

single macrocycle locked onto one thread; two macrocycles on 

one thread would constitute a [3]rotaxane. 

[193] According to Prelog,the concept of a molecular catenane was 

discussed by Willstätters prior to 1912 (see Refs. [189a,b]). The 

first synthesis of a catenane (using statistical threading with no 

assisting template effects) was achieved by Wasserman in 1960: 

a) E. Wasserman, J. Am. Chem. Soc. 1960, 82,4433 – 4434; 

proving the viability of such interlocked and otherwise 

topologically interesting molecules: b) H. L. Frisch,E. Wasserman, 

J. Am. Chem. Soc. 1961, 83,3789 – 3795; the first directed 

synthesis of a catenane was reported by Schill and Lüttringhaus 

in 1964: c) G. Schill,A. Lüttringhaus,Angew. Chem. 1964, 76, 

567 – 568; Angew. Chem. Int. Ed. Engl. 1964, 3,546 – 547; the 

first rotaxane was synthesized (using statistical methods) by 

Harrison and Harrison in 1967: d) I. T. Harrison,S. Harrison,J. 

Am. Chem. Soc. 1967, 89,5723 – 5724; e) I. T. Harrison,J. 

Chem. Soc. Perkin Trans. 1 1974,301 – 304. 

[194] Another synthetic strategy,“slippage”,theoretically provides a 

route to rotaxanes under thermodynamic control. However,the 

chemical assemblies prepared thus far by this route clearly do 

not satisfy the structural requirements of a rotaxane since the 

components can be separated from each other without breaking 

covalent bonds. Rather they are pseudorotaxanes— 

threaded host–guest complexes—which are (reasonably) kinetically 

stable at room temperature. The misclassification (see 

Ref. [182]) is not normally an issue because the physical 

behavior of kinetically stable pseudorotaxanes generally mir- 


175

Reviews 

rors that of rotaxanes. However,it increasingly appears to be 

confusing nonspecialists into thinking that rotaxanes are 

supramolecular species or that pseudorotaxanes that are not 

kinetically stable can act as molecular machines. Slippage could 

be used as a strategy to form rotaxanes if the stabilization 

gained from the ring binding on the thread was sufficient to 

mean that covalent bond breaking is less energetically demanding 

than dethreading of the rings over the stoppers. However,to 

date no structures of this type have been reported. 

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Hubin,D. H. Busch,Coord. Chem. Rev. 2000, 200,5–52; for 

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Dietrich-Buchecker,G. Rapenne,J.-P. Sauvage,Coord. Chem. 

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K. S. Chichak,A. J. Peters,J. F. Stoddart,Acc. Chem. Res. 2005, 

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for accounts focusing on the synthesis of interlocked molecules 

templated by a combination of hydrogen bonds and p– 

p interactions,see: n) D. Philp,J. F. Stoddart,Synlett 1991, 

445 – 458; o) J. F. Stoddart, Chem. Br. 1991, 27,714 – 718; 

p) F. M. Raymo,J. F. Stoddart,Pure Appl. Chem. 1996, 68, 

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Eur. J. 1997, 3,1933 – 1940; r) C. G. Claessens,J. F. Stoddart,J. 

Phys. Org. Chem. 1997, 10,254 – 272; s) F. M. Raymo,J. F. 

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Glink,J. F. Stoddart,Pure Appl. Chem. 1998, 70,419 – 424 (the 

latter also contains a brief account of templated synthesis based 

on ammonium ion/crown ether hydrogen bonds); for accounts 

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architectures,see: u) R. Jäger,F. Vögtle,Angew. Chem. 

1997, 109,966 – 980; Angew. Chem. Int. Ed. Engl. 1997, 36,930 – 

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Deegan, Angew. Chem. 1995, 107,1324 – 1327; Angew. Chem. 

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Smart,M. D. Deegan,J. Am. Chem. Soc. 1996, 118,10662 – 

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Teat,J. K. Y. Wong,F. Zerbetto,J. Am. Chem. Soc. 2002, 124, 

225 – 233; z) V. Aucagne,D. A. Leigh,J. S. Lock,A. R. Thomson, 

J. Am. Chem. Soc. 2006, 128,1784 – 1785; for phenolate 

templates,see: aa) C. Seel,F. Vögtle,Chem. Eur. J. 2000, 6,21 – 

24; for a discussion of the template-directed construction of 

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Ref. [190] and ab) T. J. Kidd,D. A. Leigh,A. J. Wilson,J. Am. 

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ad) J. S. Hannam,T. J. Kidd,D. A. Leigh,A. J. Wilson,Org. 


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A. Morelli,S. Parsons,J. K. Y. Wong,Angew. Chem. 2004, 116, 

1238 – 1241; Angew. Chem. Int. Ed. 2004, 43,1218 – 1221; for a 

route to rotaxanes that only requires a catalytic amount of 

template,see: af) V. Aucagne,K. D. Hänni,D. A. Leigh,P. J. 

Lusby,D. B. Walker,J. Am. Chem. Soc. 2006, 128,2186 – 2187. 

[196] With the notable exception of the earliest statistically constructed 

[2]rotaxanes (see Refs. [193d,e]) and those assembled 

by covalent bond-directed synthesis (a) G. Schill,H. Zollenkopf, 

Justus Liebigs Ann. Chem. 1969, 721,53 – 74; b) K. 

Hiratani,J. Suga,Y. Nagawa,H. Houjou,H. Tokuhisa,M. 

Numata,K. Watanabe,Tetrahedron Lett. 2002, 43,5747 – 5750; 

c) N. Kameta,A. Hiratani,Y. Nagawa,Chem. Commun. 2004, 

466 – 467; d) Y. Nagawa,J. Suga,K. Hiratani,E. Koyama,M. 

Kanesato, Chem. Commun. 2005,749 – 751),there are few 

examples of rotaxanes without significant noncovalent recognition 

elements between macrocycle and thread; however,see: 

Ref. [195aa,af] and e) G. M. Hübner, J. Glaser, C. Seel, F. 

Vögtle, Angew. Chem. 1999, 111,395 – 398; Angew. Chem. Int. 

Ed. 1999, 38,383 – 386; f) C. Reuter,W. Wienand,G. M. 

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[197] P. L. Anelli,N. Spencer,J. F. Stoddart,J. Am. Chem. Soc. 1991, 

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[198] a) P. R. Ashton,D. Philp,N. Spencer,J. F. Stoddart,J. Chem. 

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[201] The rate of submolecular motion in the analogous benzylic 

amide catenanes exhibits similar solvent effects,see: a) D. A. 

Leigh,A. Murphy,J. P. Smart,M. S. Deleuze,F. Zerbetto,J. 

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[202] P. Ghosh,G. Federwisch,M. Kogej,C. A. Schalley,D. Haase, 

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[203] Cleavage of covalent bonds,in the form of acid-mediated Nbutyloxycarbamate 

cleavage to reveal an ammonium binding 

site has been used to initiate degenerate shuttling,see: J. G. 

Cao,M. C. T. Fyfe,J. F. Stoddart,G. R. L. Cousins,P. T. Glink, 

J. Org. Chem. 2000, 65,1937 – 1946. 

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b) for another system in which either metal coordination or 

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[205] D. A. Leigh,A. Troisi,F. Zerbetto,Angew. Chem. 2000, 112, 

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[206] Even in 1991,when reporting the first degenerate molecular 

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desymmetrize the molecular shuttle by inserting nonidentical 



stations along the polyether thread in such a manner that 

these different stations can be addressed selectively by 

chemical,electrochemical,or photochemical means and so 

provide a mechanism to drive the bead to and fro between 

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[207] a) A. C. Benniston,A. Harriman,Angew. Chem. 1993, 105, 


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[210] a) H. Murakami,A. Kawabuchi,K. Kotoo,M. Kunitake,N. 

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[212] Intriguingly,insertion of an alkyl spacer beyond the viologen 

units restores the ability to undergo E!Z photoisomerization, 

concomitant with shuttling of the ring to this remote site (see 

Ref [210b]). Shuttling back to the central unit does not occur 

immediately on re-isomerization back to the E isomer,on 

account of the large kinetic barrier for passage over the 

viologen unit. It may be appropriate to regard this analogue, 

and therefore indeed 66,as two-station shuttles. However,any 

favorable interactions with the alkyl “stations” in either case 

are rather weak and poorly defined. 

[213] A molecular mechanics study of 66 yielded results consistent 

with the experimental observations for this shuttle. Although 

no comment is made of it,the optimized Z-66 co-conformation 

has the wider 3-rim of the a-CD closest to the azobenzene unit, 

in contrast to the experimental findings for 67,see: K. Sohlberg, 

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[214] For examples with cyclodextrin macrocycles,see Ref. [50]. 

Similar effects have been observed when forming either 

pseudorotaxanes or rotaxanes by threading though the cavity 

in calixarenes,see: Ref. [181g] and A. Arduini,F. Ciesa,M. 

Fragassi,A. Pochini,A. Secchi,Angew. Chem. 2005, 117,282 – 


[215] Providing the chemical reaction is fast with respect to the 

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[216] R. A. Bissell,E. Córdova,A. E. Kaifer,J. F. Stoddart,Nature 

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[217] The subsequent proliferation of molecular machines based on 

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Berardi,E. Córdova,M. O. de Olza,A. E. Kaifer,J. D. 

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computational methods by which the related bistable shuttles 

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[220] Terms such as “all-or-nothing” or “quantitative” are inappropriate 

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[221] Molecular mechanics calculations on both forms of this system 

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[222] For an example of another pH-switched shuttle from the 

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[226] Shuttle 69 also shows a certain degree of electrochemical 

switching in the deprotonated state when electrochemical 

reduction of the bipyridinium unit causes movement of the 

macrocycle back towards the amine moiety. In this state 

however,the electron-rich macrocycle has no significant 

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[227] H.-R. Tseng,S. A. Vignon,J. F. Stoddart,Angew. Chem. 2003, 


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Reviews 

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2555 – 2564; f) A. H. Flood,A. J. Peters,S. A. Vignon,D. W. 

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N. N. P. Moonen,B. W. Laursen,Y. Luo,E. DeIonno,A. J. 

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[230] For an independent computational study of this system which 

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X. G. Zheng,K. Sohlberg,J. Phys. Chem. A 2003, 107,1207 – 

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[232] For other examples of electrochemically switched shuttles,see: 

a) R. Ballardini,V. Balzani,W. Dehaen,A. E. Dell Erba,F. M. 

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[236] The binding of Cd II ions to the BPA-glycine carbonyl oxygen 

atom lowers the pK a value of the adjacent NH proton,thus 

allowing selective deprotonation at this site. Model studies also 

show that deprotonation cannot occur while the macrocycle 

resides on the glycylglycine station and so the reaction must 

only occur in the minor translational isomer; once again,it is 

important to remember that the co-conformations in a simple 

[2]rotaxane are always in equilibrium. 

[237] D. A. Leigh,E. M. PØrez,Chem. Commun. 2004,2262 – 2263. 

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[244] Heat has been used to bring about cis!trans isomerization in 

80 that results in a concomitant net change of the position of the 

ring (see Ref. [240]),while a temperature increase has also 

been used to overcome a significant kinetic barrier to shuttling 

following a chemical change in a kinetically stable pseudorotaxane 

(see Ref. [188b]). In neither of these cases is the 

process reversible on cooling the material without some other 

stimulus being applied. In a number of the p-donor-/pacceptor-based 

molecular shuttles the population distribution 

can exhibit a certain degree of temperature sensitivity. This can 

occur when a large difference exists in the enthalpy of binding 

at each station and/or because of the formation of “alongside” 

interactions between the unoccupied electron-rich station and 

the outer surface of the positively charged macrocycle,which 

incurs entropic losses and enthalpic gains. See,for example, 

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and a significant number of these degrees of freedom must be 

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[247] A series of theoretical designs for entropy-driven mechanical 

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[248] There are some clear limitations in using temperature as an 

entropy-driven switching mechanism: for example,it would be 

very difficult to address a small region of a larger array of 

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[249] T. Da Ros,D. M. Guldi,A. F. Morales,D. A. Leigh,M. Prato, 

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[254] A series of stimuli-responsive molecular shuttles have been 

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states when operating in self-assembled monolayers,a 

polymer electrolyte,or at low temperatures (see Refs. [191ad, 

228f,i] and Sections 8.1 and 8.3). This may account for the 

junction hysteresis observed in solid-state electronic devices 

that utilize such rotaxanes (see Section 8.3.1). Kinetically stable 

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[269] As well as demonstrating co-conformational preferences for 

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